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Pentraxin-3 (PTX3) is a glycoprotein involved in inflammation and immune regulation of cancer. The aim of this study was to evaluate the serum PTX3 level in patients with colorectal cancer (CRC) and analyze its prognostic significance.A total of 263 consecutive patients underwent radical resection for primary CRC and 126 healthy controls were enrolled in this study. Serum PTX3 level was measured within the day before surgery though enzyme-linked immunosorbent assays, comparing with the level of healthy control. Baseline demographic and clinical characteristics were recorded. The association between serum PTX3 level and survival outcome was analyzed by the Kaplan–Meier with Log-Rank test and Cox regression methods.Mean serum PTX3 level in CRC patients was higher than that of healthy control (13.8 ± 3.2ng/mL versus 3.3 ± 1.2ng/mL, P < .001). Finally, 55 (20.9%) patients out of all 263 patients studied had died during following-up period. All patients were divided into 2 groups using the optimal cutoff value (12.6 ng/mL) of PTX3 level using a sensitivity of 68.0% and a specificity of 71.7% as optimal conditions from receiver operating curve analysis. Patients with a PTX3≥12.6ng/mL had poorer 5 years overall survival rate (76.6% versus 67.8%, P = .025) patients with a PTX3 < 12.6ng/mL in univariate analysis and serum PTX3 level also been confirmed as an independent predictor for survival for CRC in multivariate analysis (Hazard ratio, 1.468; 95% [confidence interval] CI, 1.081–1.976; P < .001).Serum PTX3 level can serve as an independent prognostic biomarker for CRC patients after curative resection.