Nonsteroidal antiinflammatory drugs (NSAIDs) may play a role in breast cancer prevention; however, breast cancer subtypes and lifestyle/host factors may influence their impact. During 1996-1998 in Canada, the authors examined the association between regular NSAID use (defined as daily use for at least 2 months) and breast cancer risk by estrogen receptor (ER) and progesterone receptor (PR) status, cigarette smoking exposure, and history of arthritis. Breast cancer cases (n = 3,125, including 1,600 ER+PR+ and 591 ER-PR-) and an age-matched, random sample of controls (n = 3,062) completed a general risk factor questionnaire, including detailed questions on prescription and nonprescription NSAID use. NSAID use was associated with reduced risk of breast cancer (odds ratio = 0.76, 95% confidence interval: 0.66, 0.88). The association was not significantly different for ER+PR+ (odds ratio = 0.71, 95% confidence interval: 0.60, 0.84) and ER-PR- cancers (odds ratio = 0.80, 95% confidence interval: 0.62, 1.03) (p(heterogeneity) = 0.66). The magnitude of the NSAID inverse association was similar for women with and without arthritis and across smoking strata (risk estimates ranged from 0.74 to 0.84). Breast cancer risk tended to decrease with increasing duration of NSAID use and was generally lowest for >or=7 years of use, and both acetylsalicylic acid and non-acetylsalicylic acid use were associated with reduced risks.