To assess potential clinical applications for molecular genetic markers associated with human esophageal tumorigenesis, ten patients with primary esophageal adenocarcinomas were studied prospectively to evaluate expression of the p53 and H-ras genes. Total RNA was extracted from tumor, Barrett's epithelium, and histologically normal esophageal mucosa obtained at surgical resection, and gene expression investigated by Northern blot analysis. p53 was overexpressed, relative to normal tissue from the same patient, in seven tumor and six Barrett's specimens, whereas high levels of H-ras were found in only four tumor and one Barrett's specimen. Clinical correlative data were obtained for all patients, with a median follow-up of 14 months. Advanced pathologic stage was associated with poor survival. No association was found between gene expression and outcome. Three patients with low p53 and H-ras levels developed metastatic disease 7 to 12 months following resection. We conclude that both p53 and ras are implicated in the progression of Barrett's epithelium to invasive cancer, and that further clinical correlative studies are warranted to evaluate potential clinical application for such molecular markers.