We have shown previously that human sperm bind and enter leukocytes expressing surface HLA class II molecules. In the present study, mutant B lymphoblastoid cells and HLA-DR-transfected murine 3T3 fibroblasts are used to confirm that HLA class II molecules are somatic cell receptors for sperm. Further, for isolated HLA-DR expressed on murine cells, we show that sperm receptor activity requires the presence of sulfated carbohydrates. As carriers of multiple HLA-DR binding ligands, sperm may 1) mimic the target cell-activating effects of anti-DR antibody and 2) bind HIV through CD4-like or alternate receptors. By these or other mechanisms, sperm/somatic cell interactions in the female reproductive tract may affect fertility and potentiate the sexual transmission of AIDS.