Background: The cancer chemopreventive benefits of aspirin and nonaspirin nonsteroidal anti-inflammatory drugs (NSAIDs) are incompletely defined and may vary by smoking history. We evaluated associations between aspirin and nonaspirin NSAID use with cancer incidence and mortality stratified by smoking history in the Iowa Women's Health Study, a prospective cohort of postmenopausal women. Methods: Aspirin and nonaspirin NSAID use was self-reported by questionnaire in 1992. Cancer incidence and mortality were ascertained by annual linkage to the Iowa Surveillance, Epidemiology, and End Results Cancer Registry and death certificates. Cox proportional hazards models were used to estimate multivariable relative risks (RRs) and 95% confidence intervals (CIs). All statistical tests were two-sided. Results: During an average of 10 years of follow-up, 3487 incident cancer cases and 3581 deaths were observed in the cohort of 22507 women. Compared with nonuse, aspirin use was inversely associated with total cancer incidence (multivariable-adjusted RR = 0.84, 95% CI = 0.77 to 0.90), with age-adjusted incidence rates of 147 and 170 per 10000 person-years for ever and never users, respectively, and was inversely associated with cancer mortality (multivariable-adjusted RR = 0.87, 95% CI = 0.76 to 0.99), with age-adjusted rates of 47 and 52 per 10000 person-years. The inverse relationship was stronger among former and never smokers than current smokers, although not statistically significantly (P = .28). Aspirin use was also inversely associated with coronary heart disease mortality (multivariable-adjusted RR = 0.75, 95% CI = 0.64 to 0.89), with age-adjusted rates of 23 and 30 per 10000 person-years for ever and never users, respectively, and with all-cause mortality (multivariable-adjusted RR = 0.82, 95% CI = 0.76 to 0.89), with age-adjusted rates of 126 and 155 per 10000 person-years. Nonaspirin NSAID use was not associated with cancer incidence or mortality, coronary heart disease mortality, or all-cause mortality. Conclusions: Aspirin use, but not nonaspirin NSAID use, was associated with lower risks of cancer incidence and mortality, which was more pronounced among former and never smokers than current smokers.