This study was conducted to evaluate the expression of the presumptive tumor suppressor gene, FHIT (fragile histidine triad) and its clinical significance in non-Hodgkin's lymphoma (NHL). Nine lymphoma cell lines, 62 NHL samples including 31 diffuse large B-cell lymphomas (DLBCLs), and 10 benign hyperplastic lymph nodes were analyzed for FHIT transcription using RT-PCR, with DNA sequencing performed where aberrant transcripts were found. Immunohistochemistry (IHC) studies were conducted for evaluation of FHIT protein expression with clinical data collected for assessment of the clinical relevance of the FHIT expression in DLBCLs. Eight of nine (88.9%) cell lines showed abnormal FHIT mRNA transcription, including 4 with co-existence of normal and aberrant transcripts, and 4 with absence of mRNA expression. Abnormal FHIT mRNA expression was noted in 10 (32.3%) DLBCL patients, including 3 with loss of FHIT mRNA expression and 7 with aberrant transcripts. In all NHLs, abnormal FHIT transcripts were determined for 17 of 62 patients (27.4%). Regarding the FHIT protein expression in DLBCLs, 41.9% showed strong FHIT IHC expression (2+), where 58.1% patients revealed reduced (1+) or absence (0) of FHIT protein. Decreased FHIT protein expression was associated with a worse survival after univariate and multivariate analysis. Our result indicates that abnormal FHIT mRNA expression is noted frequently in NHL cell lines and a certain proportion of NHL patients, and decreased FHIT protein expression indicates a significantly worse prognosis in DLBCLs.