Traditional nonsteroidal anti-inflammatory drugs block cyclooxygenase (COX). They are the most widely used drugs for pain relief. They are indispensable for their effects but are condemned for their adverse drug reactions. Two COX inhibitors, acetaminophen and aspirin, are the most widely used over-the-counter drugs. They have low (but useful) therapeutic activity, but they are endowed with specific risks that are not seen with most other COX inhibitors. Both are lethal if taken in overdose. Each is stigmatized by severe adverse effects. Aspirin results in prolonged inhibition of blood coagulation, and acetaminophen can result in liver toxicity at normal dose and liver failure at higher dose. Both drugs cause many deaths every year. We recommend that the status of both drugs be changed to prescription only. Their continued availability over the counter poses an unacceptable risk to the general population.