The bcl-2 proto-oncogene and the p53 tumor suppressor gene are important determinants of tumor cell susceptibility to apoptosis, bcl-2 and mutant p53 proteins inhibit apoptosis in vitro and can provide prognostic information in certain tumor types, We analyzed bcl-2 and p53 expression in archival pancreatic (ii = 35) and ampullary (It = 6) adenocarcinomas, resected for cure, and their relationship to overall survival, Patients were treated with 5-fluorouracil and irradiation either pre- (n = 21) or postoperatively (n = 15); 5 patients received surgery alone, Using specific monoclonal antibodies, cytoplasmic bcl-2 and nuclear p53 proteins were detected in 22 of 40 (55%) and 20 of 37 (54%) tumors, respectively, No relationship was found between bcl-2 and p53 expression, Neither bcl-2 nor p53 correlated with histological response to preoperative chemoradiation. Lymph node involvement predicted poor overall survival (P = 0.02), A trend toward improved survival was seen in well-differentiated (P = 0.08) tumors and in those with increased bcl-2 expression (P = 0.06), p53 expression was not related to clinical outcome, In a multivariate analysis, nodal status was the single most important predictor of overall survival. Of note, the combined variable of bcl-2 expression and histological grade was a stronger prognostic variable than nodal status alone, Unlike nodal status, these features can potentially be evaluated in preoperative biopsy specimens.