FHIT (Fragile Histidine Triad), a putative tumor suppressor gene, was cloned from fetal brain and colon cDNA libraries. Portions of this gene are deleted in esophageal, colon, lung and breast tumors, but this gene has not been found altered in sporadic renal cell carcinomas. We report here an alternatively spliced form of this gene cloned from a kidney cDNA library. This cDNA is 1189 bp in length, and contains an additional 94 bp exon, designated exon 2a (E2a). This novel sequence is located between exon 2 and exon 3 of the FHIT gene's untranslated region and exon 2a is present in all normal kidney tissues and cell lines. Analyses performed on sporadic renal cell carcinoma (RCC) tissues and cell lines, show consistent loss of exon 8 of the FHIT cDNA in almost 60% of the cases. Interestingly, in a familial, as well as, in a metastatic RCC, derived from a patient with the sporadic form, exon 2a and exon 3 are also deleted. Northern analyses with the exon 2a of the familial and the metastatic RCC demonstrates concurrent loss of expression of a 4.4 kb transcript with the loss of the E2a sequence, suggesting that exon 2a of the FHIT gene may play an important role in the oncogenesis of renal cell carcinoma.