The development of cisplatin-based induction chemotherapy followed by surgical resection or radiation has improved the poor prognosis of stage III non-small cell lung cancer (NSCLC). In vitro studies indicate that p53 can modulate cisplatin-induced cytotoxicity, but the molecular genetic features determining response or resistance to cisplatin in vivo must be defined. For this reason, tumor specimens from 52 patients with stage IIIA NSCLC entered in a prospective clinical trial of cisplatin-based induction chemotherapy followed by surgical resection were examined for p53 expression by immunohistochemical staining before and after induction chemotherapy. p53 expression was correlated with clinical and pathological response using Fisher's exact test. No correlation was established between p53 expression and clinical response because 47 of the 52 patients studied had a major response. However, a significant association was observed between aberrant p53 expression and resistance to chemotherapy as assessed by pathological response. Only 3 of the 20 patients whose tumors exhibited a high level (+ + to + + + +) of p53 staining experienced a major (+ + + to + + + +) pathological response to chemotherapy. Only 7 of 52 cases examined before and after chemotherapy treatment exhibited a change in the level of p53 expression after cisplatin-based chemotherapy. These results indicate that cisplatin alters p53 expression infrequently and suggest a direct link between aberrant p53 expression and resistance to cisplatin-based chemotherapy in NSCLC.