Mannan-binding lectin-associated serine protease-2 (MASP-2) is the initiating enzyme of the lectin pathway of complement activation. High preoperative serum levels of MASP-2 are associated with recurrence and poor survival in patients with colorectal cancer (CRC). In this study we investigate the prognostic role of MASP-2 in patients curatively resected for primary CRC. Serum concentrations of MASP-2 were determined in 281 patients prior to surgery and 7 months postoperatively using a time-resolved immunofluorometric assay. End points were recurrent cancer and death within a median follow-up time of 7.9 years. The correlation between pre- and postoperative levels was 0.49. High postoperative levels of MASP-2 were significantly associated with poor survival [p = 0.04; hazard ratio (HR) = 1.35; 95% confidence interval (CI), 1.02-1.80] and recurrence (p = 0.01, HR = 1.6, 95% CI, 1.1-1.6). The inclusion of age, gender, tumor localization, and Dukes stage in multivariate analysis demonstrated that high MASP-2 levels were independently predictive of survival (p = 0.01; HR = 1.5, 95% CI, 1.1-2.0) and recurrence (p = 0.01, HR = 1.6; 95% CI, 1.1-2.4). Combining pre- and postoperative MASP-2 levels did not improve the prediction of survival/recurrence. High postoperative levels of MASP-2 are associated with poor prognosis in patients curatively resected for CRC. A change of the MASP-2 level from preoperative levels was not, per se, predictive of recurrent disease or survival.