Colony stimulating factor-1 (CSF1) and its receptor (CSF1-R) are important in mammary gland development and have been implicated in breast carcinogenesis. In a nested case-control study in the Nurses' Heath Study of 726 breast cancer cases diagnosed between June 1, 1992, and June 1, 1998, and 734 matched controls, we prospectively evaluated whether circulating levels of CSF1 (assessed in 1989-1990) are associated with breast cancer risk. The association varied by menopausal status (Pheterogeneity = 0.009). CSF1 levels in the highest quartile (versus lowest) were associated with an 85% reduced risk of premenopausal breast cancer [relative risk (RR), 0.15; 95% confidence interval (95% CI), 0.03-0.85; Ptrend = 0.02]. In contrast, CSF1 levels in the highest quartile conferred a 33% increased risk of postmenopausal breast cancer (RR, 1.33; 95% CI, 0.96-1.86; Ptrend = 0.11), with greatest risk for invasive (RR, 1.45; 95% CI, 1.02-2.07; Ptrend = 0.06) and ER+/PR+ tumors (RR, 1.72; 95% CI, 1.11-2.66; Ptrend = 0.04). Thus, the association of circulating CSF1 levels and breast cancer varies by menopausal status.