Our previous study showed a characteristic p53 mutational spectrum in lung tumors from lung cancer patients in the Western Pennsylvania region. To further understand the involvement of p53 mutations in lung tumor development, in this study we compared p53 mutational spectra and distribution between tumor cells taken from lung tumor tissue and histologically normal cells taken from tumor-surrounding tissue obtained from 122 lung cancer patients [67 adenocarcinomas (ACs) and 55 squamous cell carcinomas (SCCs)]. Overall, mutations were detected in exons 5-8 of the p53 gene in cell samples from 39.3% (48/122) of the patients. Twenty-four mutations were found among the ACs (35.8%, 24/67) and consisted mostly of G to T transversions at codon 248 in either only the tumor tissue (12 cases, 50%), or only the histologically normal tissue (2 cases, 8.3%), or both tissue types (10 cases, 41.7%). Among the SCCs, 24 mutations of both transition and transversion types were detected at multiple codons in either only the tumor tissue (17 cases, 70.8%), or only the histologically normal tissue (3 cases, 12.5%), or both tissues (4 cases, 16.7%). Overall, the distribution of mutations among the tumor tissue and histologically normal tissue was not significantly different between the ACs and SCCs (P > 0.05). In both groups, the mutations in the histologically normal tissue may be identical to or different from those in the tumor tissue. Therefore, p53 mutations are frequent in tumor-surrounding histologically normal tissue, and some of them might be involved in lung carcinogenesis.