Lymphocyte antigen-6 (LY-6) superfamily members are cysteine-rich, generally GPI-anchored cell surface proteins, which have definite or putative immune related roles. A cluster of five potential LY-6 superfamily members is located in the human and mouse major histocompatibility complex class III region. Comparative analysis of their genomic and cDNA sequences allowed us to carry out detailed annotations of these genes. We analyzed their mRNA expression patterns by RT-PCR performed on human and mouse cell line and tissue RNA. Sequence analysis of the transcripts revealed splice variants of all these genes in humans, and all but one in mouse. These splice forms retained introns or intron fragments, mainly generating premature stop codons, such that the only potentially functional mRNA was the predicted form. In some cases, the mis-spliced form was the most abundant form, suggesting a control mechanism for gene expression. Each gene showed mRNA expression differences between human and mouse.