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A large body of experimental data and several recent epidemiologic studies indicate that aspirin use may decrease cancer risk. The experimental studies found effects at many anatomic sites, whereas the epidemiologic studies saw the greatest effect on mortality from digestive cancers. To provide further human data, we examined the association between aspirin use and cancer risk using data from the National Health and Nutrition Examination Survey I (NHANES I) and the NHANES I Epidemiologic Follow-up Studies (NHEFS). Characterization of aspirin use was based on questions in the baseline interview asking whether subjects used aspirin during the previous 30 days. Data were available from 12,668 subjects age 25–74, at time of initial examination for NHANES I, who were followed for an average of 12.4 years. Among these subjects, 1,257 were diagnosed with cancer more than 2 years after their NHANES I examination. Incidence of several cancers was lower among persons who reported aspirin use: the incidence rate ratios (and 95% confidence intervals) for all sites combined were 0.83 (0.74–0.93), lung cancer 0.68 (0.49–0.94), breast cancer in women 0.70 (0.50–0.96), and colorectal cancer in younger men 0.35 (0.17–0.73). These findings were not readily explained by potentially confounding factors. The data suggest an association between aspirin consumption and decreased cancer incidence at several cancer sites.