An open reading frame, LMW8-DR, in the African swine fever virus (ASFV) genome possesses striking similarity to the lymphocyte membrane antigen CD2. All characterized CD2 domains, including the amino-terminal signal sequence, IgV, hinge, IgC2, stalk, transmembrane, and proline-rich carboxy cytoplasmic domains, are highly conserved in the ASFV gene. Critical residues for the binding of the lymphocyte function-associated antigen (LFA-3) and CD59 and for T-cell activation are also partially conserved. LMW8-DR is actively transcribed in ASFV-infected swine macrophages and Vero cells at late times in the infection cycle and Vero and COS cells transiently expressing the LMW8-DR open reading frame hemadsorbed swine red blood cells. The structural and functional similarities of LMW8-DR to CD2, a protein that is involved in cell-cell adhesion and immune response modulation, suggest a possible role in the pathogenesis of ASFV infection.