The central role of the liver in drug metabolism sets the stage for drug-related hepatotoxicity. The incidence of hepatotoxicity associated with non-narcotic analgesics is low, but their widespread use both prescription and over-the-counter-makes analgesic-associated hepatotoxicity a clinically and economically important problem. Hepatotoxicity is considered a class characteristic of nonsteroidal anti-inflammatory drugs (NSAIDs), despite the fact that they are a widely diverse group of chemicals. In fact, there are many differences in the incidence, histologic pattern, and mechanisms of hepatotoxicity between, as well as within, chemical classes. Most NSAID reactions are hepatocellular and occur because of individual patient susceptibility (idiosyncrasy). Aspirin, however, is a dose-related intrinsic hepatotoxin. Acetaminophen is also an intrinsic hepatotoxin but rarely demonstrates hepatotoxicity at therapeutic doses. It does cause hepatotoxicity with massive overdoses and with therapeutic doses in susceptible patients such as chronic users of alcohol. No hepatotoxicity has been reported to date with tramadol, another non-narcotic analgesic.