This is the first study that seeks to establish the prognostic value of circulating tumor cell (CTC) (determined by CellSearch system) in patients with stage III CRC. Our results suggest that given the low number of CTC in patients with localized CRC and the particular pattern of metastatic dissemination in patients with CRC, it is likely that CTC does not have a prognostic role in this setting. The prognostic role of circulating tumor cells (CTC) in early colorectal cancer (CRC) has not been determined yet. We evaluated the potential prognostic value of CTC in stage III CRC patients. Prospective multicenter study of 519 patients with stage III CRC recruited between January 2009 and June 2010. CTC were enumerated with the CellSearch System after primary tumor resection and before the start of adjuvant therapy. A total of 472 patients were included in the analysis. CTC ≥1, ≥2, ≥3 and ≥5 were detected in 166 (35%), 93 (20%), 57 (12%) and 34 (7%) patients, respectively. Median follow-up was 40 months. In the overall population, CTC ≥1 (disease-free survival (DFS): HR 0.97,P = 0.85; overall survival (OS): HR 1.03,P = 0.89), ≥2 (DFS: HR 1.07,P = 0.76; OS: HR 1.02,P = 0.95), ≥3 (DFS: HR 0.96,P = 0.87; OS: HR 0.74,P = 0.41) and ≥5 (DFS: HR 0.72,P = 0.39; OS: HR 0.48,P = 0.21) were not associated with worse DFS and OS. No clinicopathological characteristics were significantly associated with the presence of CTC. In patients with disease relapse, the proportion with CTC ≥1 was not significantly different between those with single versus multiple metastatic locations (37.9% versus 31.4%,P = 0.761). In the multivariate analysis, CTC ≥1 was not an independent prognostic factor for DFS (HR 0.97,P = 0.87) and OS (HR 0.96,P = 0.89). CTC detection was not associated with worse DFS and OS in patients with stage III CRC. Given the scarcity of CTC in these patients, it is likely that CTC determined by CellSearch system does not have a prognostic role in this setting. However, a longer follow-up is needed.