There is concern that exposures to the environmental chemicals polychlorinated biphenyls (PCBs) may contribute to breast cancer risk. An individual's susceptibility to the effects of PCBs may be partially determined by polymorphisms in the gene encoding the biotransformation enzyme cytochrome P450 1A1 (CYP1A1). PCB exposure induces CYP1A1 activity, and PCBs themselves or other xenobiotics can be metabolized to carcinogenic intermediates in the presence of the variant genotype. A previous case-control study provided evidence of an interaction between high exposures to PCBs and the CYP1A1-exon 7 polymorphism (the A to G transition at nucleotide 4889), leading to a significant increase in postmenopausal breast cancer risk. We examined the interaction of PCBs with the CYP1A1-MspI (the T to C transition at nucleotide 6235) and exon 7 polymorphisms among 367 breast cancer case-control pairs (293 postmenopausal pairs) in the Nurses' Health Study. Although there was no independent association of either the CYP1A1 variants or PCBs with breast cancer risk, the relative risk among the postmenopausal women with plasma PCB levels in the highest third of the distribution in the control group and at least one exon 7 variant allele compared with women who were homozygous for the wild-type allele and who had PCB levels in the lowest third was 2.78 (95% confidence interval, 0.99-7.82). The majority of studies have concluded that exposure to PCBs is unlikely to be a major cause of breast cancer, but these findings indicate that further studies of genetically susceptible populations are warranted.