In a case-control study of colon cancer conducted in three geographic regions of the United States, 1993 case subjects and 2410 control subjects were interviewed. In addition to queries regarding other known or suspected risk factors, subjects were asked about their use of eight drugs or drug groups. Two of these, aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs), have been inversely associated with risk in other studies. Three others–asthma medications, digitalis preparations, and phenmetrazine–were positively associated and the last three–diazepam, penicillin, and phenformin–were negatively associated with risk of colon cancer in an earlier study that screened pharmaceuticals for possible carcinogenic effects. Reported use of aspirin and NSAIDs were both inversely related to risk with essentially the same odds ratios (0.7, 95% confidence interval 0.6-0.8) for both drugs in both univariate and multivariate analyses controlling for use of each other and for other colon cancer risk factors. Subdivision by age at starting the drug, duration of use, latency interval, sex, race, family history of colon cancer, or proximal versus distal cancer revealed no substantial differences among subgroups for either aspirin or NSAIDs, but reduced risk was associated primarily with recent aspirin use. Phenformin showed a strong positive association but the data concerning this drug appeared to be inaccurate. The other drugs and drug groups showed essentially no association with colon cancer risk.