Objective: To test the hypothesis that the regular use of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) is negatively associated with the risk of subsequent colorectal cancer. Design: Case-control study with four age- and sex-matched control subjects for each incident colorectal cancer case. Population and Setting: Patient population of a large municipal teaching hospital in Atlanta, Ga. Main Outcome Measure: Odds of colorectal cancer as a function of aspirin, nonaspirin NSAIDs, and acetaminophen dispensed to the study population in the 4 years prior to incident colorectal cancer diagnosis. Main Results: The risk of colorectal cancer estimated by odds ratios decreased with inceasing days of exposure to aspirin linearly in a dose-dependent fashion (likelihood ratio statistic: for cumulative days, P<.001; for cumulative dose, P<.0001). The coefficient for days of exposure to aspirin was highly significant even when modeled as a continuous variable (P=.001). There appeared to be a threshold above which nonaspirin NSAIDs afforded protection (likelihood ratio statistic: for cumulative days, P=.021; for cumulative dose, P=.019). Acetaminophen conferred no risk reduction. Conclusion: The results of previous experimental animal models, interventional case studies, and some but not all epidemiological investigations and the present data point toward a causal relationship between NSAID use and the prevention of cancer of the large bowel and rectum. Because of the potential gastrointestinal and renal side effects of NSAID use, particularly in the elderly, chemoprevention trials are now needed to allow riskbenefit analysis in populations at high risk for colorectal cancer. © 1994, American Medical Association. All rights reserved.