Purpose: As treatment options expand for metastatic colorectal cancer (mCRC), a blood marker with a prognostic and predictive role could guide treatment. We tested the hypothesis that circulating tumor cells (CTCs) could predict clinical outcome in patients with mCRC. Patients and Methods: In a prospective multicenter study, CTCs were enumerated in the peripheral blood of 430 patients with mCRC at baseline and after starting first-, second-, or third-line therapy. CTCs were measured using an immunomagnetic separation technique. Results: Patients were stratified into unfavorable and favorable prognostic groups based on CTC levels of three or more or less than three CTCs/7.5 mL, respectively. Patients with unfavorable compared with favorable baseline CTCs had shorter median progression-free survival (PFS; 4.5 v 7.9 months; P = .0002) and overall survival (OS; 9.4 v 18.5 months; P = .0001). Differences persisted at 1 to 2, 3 to 5, 6 to 12, and 13 to 20 weeks after therapy. Conversion of baseline unfavorable CTCs to favorable at 3 to 5 weeks was associated with significantly longer PFS and OS compared with patients with unfavorable CTCs at both time points (PFS, 6.2 v 1.6 months; P = .02; OS, 11.0 v 3.7 months; P = .0002). Among nonprogressing patients, favorable compared with unfavorable CTCs within 1 month of imaging was associated with longer survival (18.8 v 7.1 months; P = .0001). Baseline and follow-up CTC levels remained strong predictors of PFS and OS after adjustment for clinically significant factors. Conclusion: The number of CTCs before and during treatment is an independent predictor of PFS and OS in patients with metastatic colorectal cancer. CTCs provide prognostic information in addition to that of imaging studies.