Mutations of the p53 gene have been found in a variety of human cancers and are implicated in the biologic functions of cancer. To investigate the clinical implications of p53 mutations in pancreatic adenocarcinoma, we examined the association of mutations of the p53 gene with patients' prognosis. Single-strand conformational polymorphism analysis and direct DNA sequencing were used to detect p53 gene mutations in 37 pancreatic adenocarcinomas. p53 gene mutations were detected in 16 (43%) of the 37 pancreatic adenocarcinomas. Direct sequencing did not reveal preferential clustering at any specific codon. There was no significant association of the presence of p53 gene mutations with histologic types, extent of tumor invasion, the presence of lymph node metastasis, or tumor stage. Univariate analysis showed that survival of patients with p53-gene-mutated tumors was significantly poorer than that of patients with p53-gene-nonmutated tumors (P = 0.02). Cox's multivariate analysis of ten clinicopathologic features including p53 gene mutations revealed that presence of p53 gene mutations (P = 0.026) and curativity of operation (P = 0.014) were independent predictors of survival. Furthermore, the survival of patients with p53-gene-mutated tumor was significantly poorer than that of patients with p53-gene-nonmutated tumors, both in patients who underwent curative operation (P = 0.04) and in patients who underwent non-curative operation (P = 0.01). These results suggested that mutations of the p53 gene might play an important role in cancer aggressiveness and could be a clinically useful predictor of prognosis in patients with pancreatic adenocarcinoma.