NSAIDs vs. Acetaminophen: Which Over-the-Counter Medicine Should I Use?

[Originally published: March 17, 2023. Updated: Sept. 23, 2025]

Pain relievers you buy at the store may be one of the first things you reach for when you hurt yourself, have a headache or backache, or feel discomfort due to some other nagging ailment that doesn’t require a visit to the doctor. Called over-the-counter (or OTC) treatments, you can get these medicines without a prescription, and they will ease pain, bring down a fever, and treat inflammation, depending on which one you take.

Most OTC medications fall into one of two categories: nonsteroidal anti-inflammatory drugs (NSAIDs) and acetaminophen, and there are different subtypes and brands (and generic options) within each of these categories.

Choosing the right OTC pain medicine can be overwhelming. The best medicine for you depends on your age, any medical conditions you may have, and other medications you may be taking. (Combining any medicines—whether they are prescription or nonprescription ones—can potentially cause an adverse reaction, or—if both contain a similar ingredient—an overdose.)

Pay attention to the cautions on the label, especially if you are pregnant, older, taking other medications, or have any health conditions. We can’t cover all of the cautions here, so it’s important to read the label carefully and talk to your doctor and/or pharmacist with questions and concerns.

As with any drug, OTC pain medicines have risks and potential side effects. And there can be health consequences if you take too much of them.

“Over-the-counter medicines can be very helpful, but people need to take them with caution,” says anesthesiologist Donna-Ann Thomas, MD, Yale Medicine’s division chief of pain medicine. “You have to remember you are still taking a medication. It’s important to follow the directions on the label, especially if you have medical issues or take other medications.”

Below, we explain the differences between the two categories of OTC medicines and answer commonly asked questions about them.

In September 2025, the Trump administration announced its conclusion that pregnant women’s use of acetaminophen, the active ingredient in Tylenol, could lead to autism in their babies. The FDA initiated the process for a related label change for acetaminophen and sent a letter alerting physicians.

However, many medical experts say the administration’s claim is unproven. The American College of Obstetricians and Gynecologists still supports the use of the drug as needed during pregnancy in moderation and after consultation with a doctor.

“The science is still far from definitive,” says Hugh Taylor, MD, chair of Obstetrics, Gynecology, and Reproductive Services for Yale Medicine. “There are studies on both sides of this issue. In light of that uncertainty, it is prudent to be careful about the use of this medication. However, there are also consequences to not treating fever and pain in pregnancy, and there are no safer alternatives.”

Dr. Taylor adds that people should not take any medication casually, especially in pregnancy. “A pregnant woman should weigh the risks and benefits and follow the advice of her obstetrician,” he says. “Judicious use of this medication is appropriate, using as low a dose as needed to be effective.”

Always follow the instructions on the label. To make this easier, an FDA regulation requires all OTC medicine labels to list information in the same order and use easy-to-understand words. Dr. Thomas recommends checking for information on who should not take the medication you are considering. Read all instructions, including how many pills you can take a day and how many hours to wait before taking the next pill.

Also, if you are choosing extra-strength medicine, do the math: For example, the recommendation for acetaminophen is no more than 4,000 milligrams (mg) in a 24-hour period for adults. Some experts, however, recommend a maximum dose of 3,000 mg per day to minimize the risk of liver damage. Regular acetaminophen is 325 mg per pill, while extra strength would be 500 mg per pill. "That means you can't take more than six extra strength Tylenol pills a day," she says.

In 2011, McNeil Consumer Healthcare, the makers of Tylenol, lowered the maximum daily dose guidelines for Tylenol Extra Strength® products from 4,000 mg per day (8 pills) to 3,000 mg per day (6 pills). They also changed the interval between doses from 2 pills every 4 to 6 hours to 2 pills every 6 hours. The company revised its dosing instructions to reduce the risk of side effects, such as liver damage, that can occur if too much acetaminophen is taken.

Yes. The two medications work differently; they can be taken in a staggered way at lower doses. A good strategy is to alternate the two medicines, taking one pill every 2 to 4 hours. For example, a four-hour dosing schedule means you might take ibuprofen at 8 a.m., acetaminophen at noon, ibuprofen again at 4 p.m., and acetaminophen again at 8 p.m., being careful not to exceed the daily dosage (as specified on the labels) for either. Consult with a health care provider before starting an alternating acetaminophen-­ibuprofen (or any other NSAID) regimen.

For each medicine, make sure the amount you are taking and the timing of the dosages are in line with instructions on the label—and check your other medications to make sure they don’t contain either of these two medicines as ingredients, Dr. Thomas adds.

Stay in touch with your doctor if you have been taking a nonprescription medicine for a long time. Some people with certain chronic conditions take these medications for years under medical guidance, Dr. Thomas explains. “The important thing is making sure your doctor knows you are taking them safely and that you're not causing harm to yourself,” she says.

If you don’t know what is causing your pain, or if you are taking an OTC pain medicine and still have pain 12 to 24 hours later, call your doctor, Dr. Thomas says. “If it's a headache, talking to the doctor—or going to the emergency room if it’s severe—is especially important.”

But, in most cases, the occasional use of an OTC pain medicine that’s appropriate for you should be fine. Making sure your doctor is aware of all the medications you are taking can help to ensure safe and effective care, she explains.

“If you have a mild fever, musculoskeletal pain, typical arthritic-type pain, joint pain or injury, or knee pain—for those kinds of things, these medications can help,” Dr. Thomas says.

The NLM provides a fact sheet with more information on OTC pain relievers.

Note: The information provided in Yale Medicine articles is for general informational purposes only. No content in the articles should ever be used as a substitute for medical advice from your doctor or other qualified clinicians. Always seek the individual advice of your health care provider with any questions you have regarding a medical condition.

This article was medically reviewed by Dr. Thomas and Michael E. Guerra, PharmD, senior clinical specialist, Surgery & Pain Management, Yale New Haven Hospital.