Src-like adaptor protein 2 (SLAP-2) is a recently characterized adaptor protein bearing sequence and structural similarity to the Src-like adaptor protein (SLAP). SLAP-2 expression is hematopoietic-specific, and it has been demonstrated to function as a negative regulator of T-cell antigen receptor (TCR)-mediated signalling by virtue of its interaction with c-Cbl. Here we report the cloning of a cDNA encoding the human homologue of SLAP-2, as well as the genomic structure of the human SLAP-2 gene. Similar to its murine counterpart, two human SLAP-2 protein isoforms exist because of alternative translation initiation, and SLAP-2 protein expression is observed in a variety of hematopoietic cell lines of both lymphoid and myeloid lineages. The human SLAP-2 gene is located on chromosome 20q, and the SLAP-2 coding region consists of seven exons. Concurrent with the cloning of the full-length SLAP-2 cDNA, a unique cDNA encoding an alternatively spliced SLAP-2 isoform has been identified, and designated as SLAP-2-v. The SLAP-2-v transcript encodes a putative protein of 210 amino acids that lacks the c-Cbl interaction region, and consequently is impaired in its ability to both bind to c-Cbl, and inhibit TCR signalling relative to SLAP-2.