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Purpose: We evaluated the prognostic and predictive value of circulating tumor cells (CTCs) hormone receptor���positive (HR��) metastatic breast cancer (MBC) patients randomized to letrozole alone or letrozole plus bevacizumab in the first-line setting (CALGB 40503). Experimental Design: Blood samples were collected at pretreatment and three additional time points during therapy. The presence of ���5 CTCs per 7.5 mL of blood was considered CTC positive. Association of CTCs with progression-free survival (PFS) and overall survival (OS) was assessed using Cox regression models. Results: Of 343 patients treated, 294 had CTC data and were included in this analysis. Median follow-up was 39 months. In multivariable analysis, CTC-positive patients at baseline (31%) had significantly reduced PFS [HR, 1.49; 95% confidence interval (CI), 1.12���1.97] and OS (HR, 2.08; 95% CI, 1.49���2.93) compared with CTC negative. Failure to clear CTCs during treatment was associated with significantly increased risk of progression (HR, 2.2; 95% CI, 1.58���3.07) and death (HR, 3.4; 95% CI, 2.36���4.88). CTC-positive patients who received only letrozole had the worse PFS (HR, 2.3; 95% CI, 1.54���3.47) and OS (HR, 2.6; 95% CI, 1.59���4.40). Median PFS in CTC-positive patients was significantly longer (18.0 vs. 7.0 months) in letrozole plus bevacizumab versus letrozole arm (P �� 0.0009). Restricted mean survival time analysis further revealed that addition of bevacizumab was associated with PFS benefit in both CTC-positive and CTC-negative patients, but OS benefit was only observed in CTC-positive patients. Conclusions: CTCs were highly prognostic for the addition of bevacizumab to first-line letrozole in patients with HR�� MBC in CALGB 40503. Further research to determine the potential predictive value of CTCs in this setting is warranted.