Mutations in the p53 tumor suppressor gene and the K-ras proto-oncogene are common genetic defects in lung cancer. Analysis of the patterns of damage in these genes may provide important insights into the mechanisms by which environmental mutagens initiate cancer. Previously, our laboratory found that a rare p53 codon 249 mutation (AGG(ARG) to ATG(MET) transversion) was present in 31% of a series of 52 large and squamous cell lung cancers from uranium miners, suggesting that this mutation might be a marker for radon exposure. In the current study, we analyzed 23 lung adenocarcinomas from the same cohort of highly exposed uranium miners. These tumors failed to show the codon 249 transversion, but 9 (39%) of 23 contained 1 or more mutations within hotspots in the K-ras gene. The results suggest that there is a histological tissue-type specificity for the codon 249 mutation; although this mutation was common in squamous and large cell tumors from very highly exposed uranium miners, it is rare in adenocarcinomas from the same cohort of miners.