Background: C-reactive protein (CRP), a marker of low-grade inflammation, has been associated with breast cancer risk, but results are scarce and inconsistent. Methods: A case-control study nested within the E3N prospective cohort included 549 postmenopausal breast cancer cases and 1,040 matched controls, all free of breast cancer at baseline. Serum levels of CRP were measured in samples collected between 1995 and 1999. Unconditional logistic regression models were used to evaluate the association between CRP and breast cancer risk, adjusting for matching factors and known breast cancer risk factors. Results: No association was observed between CRP levels and breast cancer risk overall. However, a significant interaction was observed between CRP levels and body mass index (BMI). A statistically significant increase in breast cancer risk was observed in overweight and obese women (BMI ≥ 25 kg/m2) (OR 1.92, 95 % CI 1.20-3.08 for CRP ≥ 2.5 mg/L compared with CRP < 1.5 mg/l, ptrend = 0.003, pinteraction between CRP and BMI = 0.03). Similar results were observed in women with waist circumference (WC) ≥ 88 cm (ptrend = 0.01, pinteraction = 0.06) and waist-to-hip ratio (WHR) ≥ 0.80 (ptrend = 0.06, pinteraction = 0.35). CRP levels were not associated with breast cancer risk in women with normal BMI, WC, or WHR. Conclusions: We found a positive association between CRP levels and postmenopausal breast cancer risk restricted to women with excess adiposity. The suggested relationship between low-grade inflammation, abdominal adiposity, and postmenopausal breast cancer risk deserves further investigation.