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Increased serum tumor biomarkers are usually associated with huge tumor burden, but the prognostic value of these markers remains controversial. The serum levels of carcinoembryonic antigen (CEA), nerve cell–specific enolase, and lactate dehydrogenase in 281 patients with small cell lung cancer (SCLC) were analyzed in this study. Increased serum CEA levels were observed in 92 (32.7%) patients. Survival was superior in patients with normal serum CEA levels compared with those with increased serum CEA levels. The median survival time, 2-year overall survival (OS) rate, and 3-year OS rate were 19.1 months vs 14.6 months, 42.7% vs 28.3%, and 30.6% vs 14.1%, respectively (P= 0.002). In multivariate analysis, extensive-stage (ES)-SCLC (hazard ratio [HR] = 1.936,P= 0.001), an increased serum CEA level (HR = 1.432,P= 0.021) at diagnosis, and <4 cycles of chemotherapy (ChT) (HR = 0.432,P= 0.001) were independent negative prognostic factors for the OS. Additionally, normal CEA level (HR = 1.678,P= 0.012), treatment modalities including surgery (HR = 1.595,P= 0.049), and ≥4 cycles of ChT (HR = 1.880,P= 0.004) were independent positive prognostic factors for OS in patients with local disease. In the subgroup with ES-SCLC, normal serum CEA level (HR = 1.608,P= 0.043), thoracic radiation therapy (HR = 1.744,P= 0.005), and ≥4 cycles of ChT (HR = 2.626,P= 0.001) were independent positive prognostic factors for OS.