The two lysosome-associated membrane proteins, LAMP-1 and LAMP-2, are major integral membrane proteins of the lysosomes. They also occur in the plasma membrane, where they have been discovered independently as principal lactosaminoglycan-bearing glycoproteins and as tumor antigens. Avian LAMP-2 has recently been shown to be encoded by at least three transcripts resulting in variant transmembrane and cytoplasmic domains (Hatem et al., 1995). We report isolation and characterization of chicken genomic clones indicating that the three transcripts are the result of alternative splicing of a single LAMP-2 gene. Only a single LAMP-2, homologous to chicken LAMP-2a, has been described in mammals. To ascertain whether multiple forms of LAMP-2 also occur in mammals, we cloned cDNAs encoding LAMP-2 variants homologous to avian LAMP-2b and LAMP-2c from mouse brain cDNA libraries. Thus, the family of LAMP-2 proteins is conserved from bird to mammals and the diversity is generated by alternative splicing of a single LAMP-2 gene.