Recent studies have revealed the presence of β-catenin mutations in a small subset of human and rat lung carcinomas, suggesting the involvement of the Wnt pathway in pulmonary carcinogenesis. LOH on chromosome 5q (APC locus) is frequent in lung cancer, but previous studies have found no adenomatous polyposis coli (APC) mutations. In this study, we screened 114 human lung cancer specimens for alterations in the mutation cluster region of the APC gene and in exon 3 of the β-catenin gene. SSCP followed by direct DNA sequencing revealed APC mutations in 2/44 (5%) squamous cell carcinomas, a 2-bp deletion in codon 1465 (AGT→A), and a GAA→CAA (Glu→Gln) mutation at codon 1317. One of 32 (3%) small cell lung carcinomas contained a GAA→AAA (Glu→Lys) mutation at codon 1284. Two cases with an APC mutation showed focal nuclear β-catenin staining. These results suggest that disruption of the Wnt pathway through APC mutations is infrequent, but may be involved in the pathogenesis of a small subset of human lung carcinomas.