Chromosome 3p is frequently deleted in various cancers including examples in the lung. A novel gene, termed FHIT, was recently isolated from the fragile site at 3p14.2, with aberrant transcripts being reported in lung cancer tumor specimens. To avoid overlooking tumor-specific altered transcripts due to contaminating normal cells in primary tumors, FHIT alterations were examined in 41 lung cancer cell lines in the present study. Lack of detectable expression or exclusive expression of aberrantly spliced transcripts, often accompanied by intragenic homozygous deletions, were observed in 7 of 24 non-small cell lung cancers (29%) but in 0 of 17 small cell lung cancers (0%). Extensive reverse transcription-PCR-single-strand conformation polymorphism analysis revealed polymorphisms and alternative splicing but failed to identify point mutations. These results suggest distinct mechanisms for FHIT alterations in lung tumorigenesis and that further studies of this interesting gene are warranted.