The present study is aimed to evaluate the genetic evidence for multicentricity of synchronous and metachronous multiple lung carcinomas. Nineteen cases of synchronous multiple lung carcinomas and 11 cases of metachronous multiple lung carcinomas were analyzed for p53 protein overexpression by immunohistochemistry (DO-7) and for genetic abnormality of the p53 gene by loss of heterozygosity (LOH) at chromosome 17p and by polymerase chain reaction (PCR)-single-strand conformation polymorphism (SSCP) analysis. They were also analyzed for K-ras mutation. DNA from three patients was also sequenced by the dideoxy sequencing method to confirm the presence of mutations and determine the base substitutions. Different spectrums of genetic changes, which were evaluated by a combination of p53 mutation, LOH at chromosome 17p and p53 overexpression, were observed in 11 of 19 cases of synchronous multiple lung carcinomas (57.9%) in the present study. Similarly, five of 11 cases of metachronous multiple lung carcinomas (45.4%) showed a different pattern of genetic changes. The present data suggest that some of the multiple carcinomas have different clonal origins, although their histological types are identical, and support the use of genetic markers in the differential diagnosis between metastasis and second primary carcinoma of the lung.