To determine if N-acetyltransferase 2 (NAT2) polymorphisms result in decreased capacity to detoxify carcinogenic aromatic amines in cigarette smoke, thus making some women who smoke more susceptible to breast cancer.Case-control study with genetic analyses. DNA analyses were performed for 3 polymorphisms accounting for 90% to 95% of the slow acetylation phenotype among whites.White women with incident primary breast cancer (n=304) and community controls (n=327).Neither smoking nor NAT2 status was independently associated with breast cancer risk. There were no clear patterns of increased risk associated with smoking by NAT2 status among premenopausal women. In postmenopausal women, NAT2 strongly modified the association of smoking with risk. For slow acetylators, current smoking and smoking in the distant past increased breast cancer risk in a dose-dependent manner (odds ratios [95% confidence intervals] for the highest quartile of cigarettes smoked 2 and 20 years previously, 4.4 [1.3-14.8] and 3.9 [1.4-10.8], respectively). Among rapid acetylators, smoking was not associated with increased breast cancer risk.Our results suggest that smoking may be an important risk factor for breast cancer among postmenopausal women who are slow acetylators, demonstrate heterogeneity in response to carcinogenic exposures, and may explain previous inconsistent findings for cigarette smoking as a breast cancer risk factor.