Purpose: To examine associations of prediagnosis high-sensitivity C-reactive protein (hsCRP) with breast cancer incidence and postdiagnosis survival and to assess whether associations are modified by body mass index (BMI).Methods: A prospective analysis of the Women's Health Initiative was conducted among 17,841 cancer-free postmenopausal women with baseline hsCRP measurements. Cox proportional hazards models were used to examine associations between hsCRP concentrations and (i) breast cancer risk (n cases = 1,114) and (ii) all-cause mortality after breast cancer diagnosis. HRs are per 1 SD in log hsCRP.Results: hsCRP was not associated with breast cancer risk overall [HR = 1.05; 95% confidence interval (CI), 0.98-1.12]; however, an interaction between BMI and hsCRP was observed (Pinteraction = 0.02). A 1 SD increase in log hsCRP was associated with 17% increased breast cancer risk (HR = 1.17; 95% CI, 1.03-1.33) among lean women (BMI < 25), whereas no association was observed among overweight/obese (BMI ≥ 25) women. Prediagnosis hsCRP was not associated with overall mortality (HR, 1.04; 95% CI, 0.88-1.21) after breast cancer diagnosis; however, an increased mortality risk was apparent among leaner women with higher hsCRP levels (HR, 1.39, 95% CI, 1.03-1.88).Conclusions: Prediagnosis hsCRP levels are not associated with postmenopausal breast cancer incidence or survival overall; however, increased risks are suggested among leaner women. The observed effect modification is in the opposite direction of a previous case-control study finding and warrants further investigation.Impact: Associations of higher CRP levels with incident breast cancer and survival after breast cancer may depend on BMI. Cancer Epidemiol Biomarkers Prev; 26(7); 1100-6. ©2017 AACR.