Abstract Immune-related etiologic pathways to influence invasive breast cancer risk may interact with lifestyle factors, but the interrelated molecular genetic pathways are incompletely characterized. We used data from the Women's Health Initiative Database for Genotypes and Phenotypes Study including 16,088 postmenopausal women, a population highly susceptible to inflammation, obesity, and increased risk for breast cancer. With 21,784,812 common autosomal single-nucleotide polymorphisms (SNP), we conducted a genome-wide association (GWA) gene–environment interaction (G × E) analysis in six independent GWA Studies for proinflammatory cytokines [IL6 and C-reactive protein (CRP)] and their gene–lifestyle interactions. Subsequently, we tested for the association of the GWA SNPs with breast cancer risk. In women overall and stratified by obesity status (body mass index, waist circumference, and waist-to-hip ratio) and obesity-related lifestyle factors (exercise and high-fat diet), 88 GWA SNPs in 10 loci were associated with proinflammatory cytokines: 3 associated with IL6 (1 index SNP in MAPK1 and 1 independent SNP in DEC1); 85 with CRP (3 index SNPs in CRPP1, CRP, RP11–419N10.5, HNF1A-AS1, HNF1A, and C1q2orf43; and two independent SNPs in APOE and APOC1). Of those, 27 in HNF1A-AS1, HNF1A, and C1q2orf43 displayed significantly increased risk for breast cancer. We found a number of novel top markers for CRP and IL6, which interacted with obesity factors. A substantial proportion of those SNPs' susceptibility influenced breast cancer risk. Our findings may contribute to better understanding of genetic associations between pro-inflammation and cancer and suggest intervention strategies for women who carry the risk genotypes, reducing breast cancer risk. Prevention Relevance: The top GWA-SNPs associated with pro-inflammatory biomarkers have implications for breast carcinogenesis by interacting with obesity factors. Our findings may suggest interventions for women who carry the inflammatory-risk genotypes to reduce breast cancer risk.