The chromosome region 18q21 has been shown to be frequently deleted in lung cancers. Recent identification at this locus of DPC4, a gene whose inactivation has been suggested to play a role in pancreatic carcinogenesis, prompted as to examine whether it might also be altered in lung cancers. Two missense and 2-bp frameshift somatic mutations in DPC4 were detected among 42 lung cancer specimens taken directly from patients. DPC4 mutations, however, were not present in all lung cancers carrying l8q21 deletions. These findings suggest that DPC4 may play a role in a limited fraction of lung cancers and that another tumor suppressor gene may also exist in this chromosome region.