Breast cancer is the most common cancer among women, and both low-grade inflammation and cathepsins might have important roles in breast cancer. We questioned whether prediagnostic circulating levels of C-reactive protein (CRP), cathepsin B, and cathepsin S were associated with breast cancer risk. Sixty-nine incident breast cancer cases diagnosed after blood collection and 719 controls from the Swedish Mammography Cohort were analyzed for systemic CRP, cathepsin B, and cathepsin S. Cathepsin S and inflammation (high-sensitivity CRP [hsCRP])-adjusted cathepsin S were inversely associated with breast cancer risk (cathepsin S: odds ratio [OR] for top vs. bottom tertile=0.46; 95% confidence interval [CI]=0.23-0.92; p(trend)=0.02; hsCRP-adjusted cathepsin S: OR of 0.44; 95% CI=0.22-0.87; p(trend)=0.02). hsCRP was significantly associated with increased breast cancer risk (OR for top vs. bottom tertile=2.01; 95% CI=1.02-3.95; p(trend)=0.04). No significant association was observed between cathepsin B and breast cancer risk (OR for top vs. bottom tertile=0.67; 95% CI=0.32-1.40; ptrend=0.30). These observations lead to the hypothesis that levels of cathepsin S and hsCRP observed in women who later developed breast cancer may provide prognostic information regarding tumor development and need to be evaluated in prospective studies.