In this study, we examined the expression of esophageal cancer-related gene 4 (ECRG4) mRNA and evaluated its clinical significance in esophageal squamous cell carcinoma (ESCC). ECRG4 mRNA expression was quantified by real-time RT-PCR in 63 ESCC and corresponding normal esophageal mucosal samples. ECRG4 mRNA expression levels were significantly lower in ESCC tissues compared with corresponding normal esophageal mucosa (P<0.0001), in patients with locally invasive T2-4 tumors compared with less invasive T1 tumors (P=0.0229) and in stage 4 tumors compared with stage 0-3 tumors (P=0.0120). Furthermore, low ECRG4 mRNA expression levels were associated with significantly shorter survival after surgery compared with high ECRG4 mRNA expression levels (P=0.0150) in ESCC patients. On the basis of multivariate analysis, we conclude that ECRG4 mRNA expression level could be a candidate for an independent prognostic factor for ESCC patients.