The aim of this study was to clarify whether preoperative squamous cell carcinoma-antigen messenger RNA (SCC-Ag mRNA) level in peripheral blood can be used to predict tumor recurrence after curative resection for esophageal squamous cell carcinoma.A prospective analysis was conducted for 46 consecutive patients who underwent curative esophagectomy and who had no residual tumor. The SCC-Ag mRNA level in the peripheral blood of each patient was measured preoperatively by using quantitative reverse transcriptase-polymerase chain reaction. Median follow-up period was 34 months.Receiver operating characteristic analysis demonstrated that the optimal cutoff level of SCC-Ag mRNA was 40. Patients were divided into the high SCC-Ag mRNA level group (n = 14) and the low SCC-Ag mRNA level group (n = 32). The cumulative probabilities of tumor recurrence were higher in the high SCC-Ag mRNA level group (probability of recurrence was 71% at 2 years) than in the low group (22% at 2 years; P = .0005). SCC-Ag mRNA level (relative risk, 3.00; 95% confidence interval, 1.05-8.54; P = .040) was the strongest independent predictor of recurrence by multivariate analysis.Preoperative SCC-Ag mRNA levels in the peripheral blood are the best predictive factor for recurrence in patients with esophageal squamous cell carcinoma who undergo curative resection (R0).