Abnormalities of fragile histidine triad (FHIT) and TP53 have been found frequently in nonsmall cell lung cancers. In the current study, 263 primary nonsmall cell lung cancers were investigated for the expressions of Fhit and p53 by immunohistochemistry. Marked reduction of Fhit immunoreactivity (<10% positivity) in 156 (59%) tumours and overexpression of p53 protein (>10% positivity) in 89 (34%) tumours were found. Reduced Fhit expression was also noted in most squamous cell carcinomas (80 out of 99, 81%), and in a smaller fraction of adenocarcinomas (76 out of 164, 46%; P<0.001). p53 nuclear staining was demonstrated in 54 out of 99 (55%) squamous cell carcinomas and in 35 out of 164 (21%) adenocarcinomas (P<0.001). The loss of Fhit expression and p53 overexpression was significantly more common in tumours occurring in smokers (93 out of 113, 82% and 56 out of 113, 50%) than in those of nonsmokers (63 out of 150, 42%; P<0.001 and 33 out of 150, 22%; P<0.001). Notably, p53 overexpression was associated with distant metastasis of patients in the whole series (P=0.027) and in adenocarcinoma (P=0.001). It was also associated with a poorer survival of patients with adenocarcinoma (P=0.032).