There is evidence that adipokines such as leptin and adiponectin may influence breast tumor development. We conducted a nested case-control study using women in the American Cancer Society Cancer Prevention Study II to examine the association between postmenopausal breast cancer and variability in the genes encoding leptin, the leptin receptor, adiponectin, adiponectin receptor 1, and adiponectin receptor 2. Using 648 cases and 659 controls, we found no statistically significant (P < 0.05) associations between breast cancer risk and any of the single nucleotide polymorphisms. Individual odds ratios ranged from 0.93 to 1.06. We found no evidence of effect modification by body mass index, adult weight gain, location of weight gain, or physical activity. Although we cannot rule out that these genes are involved in gene-gene or gene-environment interactions, our results suggest that individual single nucleotide polymorphisms in these genes do not substantially affect postmenopausal breast cancer risk.