Not much attention has been given to drug use and risk of colorectal cancer. We investigated the issue in an 18-year prospective cohort study of 5249 Copenhagen men aged 40–59 years. Potential confounders included were tobacco smoking, alcohol consumption, coffee drinking, physical activity, and social class. Colon cancer was diagnosed in 51 men, rectal cancer in 42 (all adenocarcinomas). Estimated from a Cox proportional hazards regression equation, use of antihypertensive medicine was highly significantly associated with risk of colon cancer; relative risk (95% confidence limits) was 3.5 (1.6–7.5) (p = 0.001). Frequent use of minor tranquilizers or sleeping pills was also associated with a highly significantly increased risk of colon cancer; relative risk was 3.2 (1.6–6.6) (p = 0.002). In contrast, there was no such association with rectum cancer. We suggest that use of antihypertensive medicine and use of minor tranquilizers or sleeping pills may be strong risk factors for colon cancer.