Mutations of the p53 tumor suppressor gene are the most frequent genetic alterations detected in human lung cancer. To assess the pathogenic significance of p53 gene alterations in Chinese non-small cell lung cancer (NSCLC), 74 paired samples of primary lung cancer and normal lung tissue far away from the cancer were analyzed for mutations of the p53 gene (exons 5-8) using exon-specific PCR, single-strand conformation polymorphism (PCR-SSCP). p53 mutations were observed in 55.4% (41/74) of the samples. No linkages were detected between the incidence of p53 mutations and histological type, lymph node metastasis, age or sex. Significant association between p53 mutations and degree of differentiation in adenocarcinomas, not in squamous cell carcinomas, was observed. The frequency of p53 mutations in smokers (65.3%) was higher than in nonsmokers (33.3%) and reached statistical significance. We also found p53 mutations in 6/7 samples which had tissue invasion and distant metastasis. These results suggest that smoking could be an important factor in lung carcinogenesis, p53 mutation is a worse prognosis indicator in adenocarcinomas and related to high aggressive behavior of human lung cancer.