Human membrane cofactor protein (MCP) is a widely distributed cell-associated complement-regulatory protein, and recent findings suggest that MCP may be involved in sperm-egg interaction. We have isolated four cDNA clones and one reverse transcriptase-PCR product homologous to human MCP from guinea pig testis. These clones defined five isoform classes generated from a single copy gene by alternative splicing. Reverse transcriptase-PCR revealed that two classes for the clones termed GMP1 and GM2 were predominant. GMP1 consisted of four short consensus repeats (SCRs), regions corresponding to the human serine/threonine/proline-rich C (STP(C)) domain and a human region of unknown significance, a hydrophobic region presumed to be a transmembrane domain, and a cytoplasmic region. Identity with human MCP in the SCR region was 56% at the amino acid level and 71% at the nucleotide level. GM2 had the same structure as GMP1, except that it lacked the fourth SCR, which is presumed to be essential for C3b binding of human MCP. Northern blotting analysis of various tissues revealed a significant level of MCP transcripts in testis. Guinea pig MCP is likely to have only one STP domain that is homologous to human STP(C) and is similar in this respect to human spermatozoa MCP. Gene analysis revealed a single base deletion and a lack of consensus sequences for splicing in the guinea pig regions corresponding to human STP(A) and STP(B), respectively. These results suggest that guinea pig MCP plays a more restricted role in reproduction than does human MCP.