Three patients with Barrett's esophagus who had cytogenetic abnormalities detected in their metaplastic epithelium developed high-grade dysplasia or adenocarcinoma during prospective surveillance over a period of 1.5 to 6 years. In the 3 cases, cytogenetic abnormalities that were associated with the most advanced histological lesions were present in samples obtained 11, 25, and 48 months prior to the diagnosis of high-grade dysplasia or carcinoma. In a fourth patient, marker chromosomes found in a Barrett's adenocarcinoma were also present in an esophageal region spatially removed from the tumor. In all four patients, clonal cytogenetic abnormalities were present in samples obtained at widespread locations in the Barrett's segment. These observations suggest that in some patients with Barrett's esophagus clonal proliferations arise in regions of benign histology and spread to involve large areas of Barrett's mucosa. These clones persisted when the disease progressed to high-grade dysplasia or adenocarcinoma.