The p53 tumor suppressor gene has recently been implicated in the pathogenesis of human esophageal cancer. To assess potential clinical applications for this molecular marker, 52 patients with primary esophageal adenocarcinoma were studied prospectively. p53 protein accumulation was evaluated immunohistochemically in surgically resected esophageal tissues, and correlated with clinicopathologic findings and survival. All patients underwent total esophagectomy with reconstruction, completely resecting all gross disease. Immunopositivity was seen in 28 of 52 (54%) primary adenocarcinomas, and was associated with a trend towards reduced postoperative survival (P = 0.06; log-rank). Regional lymph node metastases were found in 30 (58%) patients. Thirteen of 30 (43%) regional lymph node metastases were immunopositive, which was the most significant predictor of overall survival by univariate (P = 0.02; log-rank) and multivariate analysis (P = 0.05; Cox regression). This study further implicates p53 in esophageal tumor development and progression. The immunohistochemical finding of p53 protein in primary esophageal adenocarcinomas and regional lymph node metastases appears to be associated with reduced overall survival for this disease. If these preliminary observations are confirmed in larger prospective studies, p53 may prove to be a clinically useful molecular marker in future clinical trials of esophageal cancer.