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The human ZP3 gene, encoding the glycoprotein responsible for sperm-egg recognition, has been cloned using mouse ZP3 DNA as a probe. Genomic and cDNA cloning revealed eight exons, spread over 18 kb, encoding a protein of 424 amino acids with a 67% homology to mouse and hamster ZP3. Southern blotting, gene cloning, and sequence analysis were used to show that ZP3 is not a single-copy gene and that the human genome contains a second polymorphic locus which, due to an extra G residue in exon 8, has the potential to encode a truncated protein of 372 amino acids. Direct sequence analysis of polymerase chain reaction-amplified exon 8 DNA of 56 individuals of various human populations revealed three different sequence patterns: one containing only ZP3-424-coding sequences and two containing ZP3-424- and ZP3-372-coding DNA. The distribution of these three sequence patterns is significantly different between the Caucasian and Japanese populations, as indicated by ZP3-372 allele frequencies of 69 and 21%, respectively. Isolation of ZP3-424 and ZP3-372 cDNAs suggests that both loci represent functional transcription units. Therefore, it is hypothesized that throughout the human population during oogenesis ZP3 is translated from mRNAs derived from two to four transcription units. Provided that ZP3-372 mRNA is translated in vivo, corresponding differences in ZP3-372 protein levels might have an impact on human zona pellucida composition.