Barrett esophagus (BE) is a condition in which the normal squamous epithelium of the esophagus is replaced by a metaplastic columnar epithelium. BE is a premalignant lesion that represents the initial step in a metaplasia-dysplasia-carcinoma sequence. In the present study, amplification of the proto-oncogene c-myc was determined by means of differential polymerase chain reaction analysis of metaplastic specialized epithelium, low-grade dysplasia, high-grade dysplasia, and invasive adenocarcinoma obtained by microscopic dissection of 43 esophagectomy specimens. Amplification of c-myc was found in none of 29 specialized epithelial specimens, none of 23 low-grade dysplasia specimens, 6 of 24 high-grade dysplasia specimens, and 17 of 39 adenocarcinoma specimens. Our data indicate that amplification of c-myc is a late event in the metaplasia-dysplasia-carcinoma sequence in BE. Furthermore, determination of c-myc amplification may help identify high-risk patients who would benefit from intensified endoscopic surveillance or from immediate treatment.