We have isolated a series of cross-hybridizing cDNA clones, as a group designated as NKG5, from a human natural killer (NK) cell clone cDNA library. These clones show a high degree of homology with a previously described gene, 519, which was thought to be T cell specific. A comparison of the full-length cDNA sequence of NKG5 and the published sequence of 519 shows that NKG5 lacks a 242-base segment that is found in 519 and that this deletion leads to the use of a different putative translational start codon. Unlike 519, the predicted NKG5 polypeptide has an NH2-terminal sequence that is strongly hydrophobic, characteristic of a signal peptide, and lacks any additional hydrophobic regions in the remainder of the peptide, suggesting that NKG5 encodes a secreted protein. Both NKG5 and 519 are expressed in NK and T cells but not in a variety of other hematopoietic cell lines. NKG5 is an abundant transcript and its level of expression is about 40 times that of 519 in NK and T cells. Southern blot and DNA sequence analyses suggest that NKG5 and 519 mRNAs are transcripts from a single gene that has allelic polymorphism.