Until now it was assumed that the murine poliovirus (PV) receptor homolog gene (MPH) had been identified. Alternative splicing of MPH transcripts generates two glycoproteins named MPH alpha and MPH beta which share an identical N-terminal region composed of three immunoglobulin (Ig)-like domains and different C-terminal regions. Using a degenerate PCR strategy, we describe the identification of a second human PVR-related gene (PRR2), which encodes two glycoproteins, PRR2 alpha (short form) and PRR2 delta (long form). They present 69 and 73% identity with MPH alpha and MPH beta, respectively. In contrast, the human PVR protein exhibits 51% identity which is moreover restricted to the three Ig domains of the murine protein. We therefore propose that PRR2, and not PVR, is the true human homolog of MPH. In addition, Northern blot analysis showed that two mRNA isoforms of 3.0 kb (PRR2 alpha) and 4.4 kb (PRR2 delta) are ubiquitously found in various normal human tissues. In situ hybridization allowed us to map PRR2 to the 19q13.2-q13.4 bands of the human genome, in the same chromosomal region as PVR.