Gene amplification is a relatively frequent event in human malignant tumors and is believed to play an important role in tumor progression. The int-2 and erbB genes are amplified more frequently than any other genes in human esophageal cancer. In order to investigate the correlation between these two proto-oncogenes and the clinical behavior of esophageal cancer, we examined DNA amplification of int-2 and erbB and analyzed their relationship to clinicopathological variables. Genomic DNA was extracted from 21 esophageal squamous carcinomas and normal esophageal mucosa, as well as from 4 metastatic tumors. We used Southern blot analysis for detection of gene amplification. Amplification of int-2 was observed in 13 of 21 cases (62%) and in all the metastatic tumors (4/4; 100%). We found a significant correlation between amplification of int-2 and the length of the primary lesion. Amplification of erbB was detected in 3 of 18 patients (17%). All patients who showed amplification of erbB also demonstrated amplification of int-2. These results suggest that amplification of int-2 or neighboring genes on 11q may participate in tumor progression and metastasis in patients with esophageal squamous cancer.