Use of non-steroid anti-inflammatory drugs (NSAIDs) has been associated with decreased risk of breast cancer in epidemiological studies. Thus, a high-inflammatory response may be associated with increased breast cancer risk. It is thus possible that genetic variations leading to a modified inflammatory response will influence breast cancer risk. The purpose of this study was to determine if polymorphisms associated with an altered inflammatory response are associated with breast cancer risk, and to investigate the possible interaction with lifestyle factors such as alcohol use, smoking and NSAID use. We matched 361 female breast cancer cases with 361 controls, nested within the prospective 'Diet, Cancer and Health' study. Carriers of the variant Ala-allele of PPAR gamma 2 Pro(12)Ala were at lower risk of breast cancer (IRR = 0.67, 95% CI = 0.46-0.97). This was primarily due to an interaction with alcohol consumption. Alcohol consumption was associated with a 1.21-fold increased risk of breast cancer per 10 g alcohol/day (95% CI = 1.06-1.35) among homozygous wild-type carriers, whereas alcohol was not associated with breast cancer risk among variant allele carriers (P for interaction = 0.005). Non-users of NSAID, who were carriers of the variant allele of PPAR gamma 2 Pro(12)Ala, were at lower risk of breast cancer (IRR = 0.44; 95% CI = 0.26-0.73) compared with non-users carrying wild-type alleles (P for interaction = 0.03). No effects were found for IL6 G-174C, IL8 T-251A and COX2 T8473C. Our results suggest that PPAR gamma 2 Pro(12)Ala is an important determinant in alcohol mediated breast carcinogenesis. We also observe interaction between NSAID, alcohol consumption and PPAR gamma 2 Pro(12)Ala genotype in relation to breast cancer risk.