Background: Although epidermal growth factor receptor (EGFR) inhibitor treatment showed modest response in several clinical trials in esophageal squamous cell carcinoma (ESCC) patients, it has been reported that the frequency of EGFR mutations varied largely. The aim of this study was to investigate the existence of EGFR mutations in Chinese esophageal squamous cell carcinomas. Methods: Formalin-fixed paraffin-embedded surgically resected tumor samples were obtained from 127 randomly selected Chinese patients with ESCC. The most common EGFR mutations, including in-frame deletions in exon 19 and base substitutions in exon 21, were detected by denaturing high performance liquid chromatography (DHPLC) and direct sequencing simultaneously. K-RAS mutations in codons 12 and 13 were detected by direct sequencing. Results: In this study, L858R missense mutations of the EGFR gene were found in 8 out of 127 patients (6.3%) by DHPLC but no mutation was observed by direct sequencing. In addition, K-RAS mutation was detected in 2 out of 127 (1.6%) patients by direct sequencing. Conclusions: The incidence of EGFR mutations was relatively high using DHPLC method but no mutation with direct sequencing in Chinese ESCC patients.