Understanding molecular interactions between human leukocytes and porcine endothelium is important for the future success of pig-to-human xenotransplantation. Here we describe the analysis of pig intercellular adhesion molecule-2 (ICAM-2). A 1020-basepair ICAM-2 cDNA generated from pig lung RNA contained an open reading frame (ORF) encoding a 277-amino-acid protein with six potential N-linked glycosylation sites. The mature protein sequence was 55% identical to human ICAM-2, with conservation of five out of six residues critical for binding of the human protein to its ligand LFA-1. Northern blot analysis identified ICAM-2 transcripts of 4.0 and 1.4 kb in cultured pig endothelial cells and mRNA was detected in pig lung, spleen, kidney, liver and heart by RT-PCR. The gene structure and endothelial expression of pig ICAM-2 were strikingly similar to those of its human and mouse counterparts. However, unlike human ICAM-2, expression of pig ICAM-2 on cultured endothelial cells was not down-regulated by treatment with the inflammatory cytokines TNF-alpha and IL-1beta. Pig ICAM-2 expressed on stable transfectants supported firm adhesion of cells expressing human LFA-1. This conservation of function across the species barrier suggests that pig ICAM-2 plays a role in the cellular interactions associated with xenograft rejection.