ABSTRACT:The involvement of antigens coded by the major histocompatibility complex in alloimmunization of guinea pigs with sperm has not been fully explored. Some of the “in vitro” correlates of cell‐mediated immunity, such as the lymphocyte transformation test in presence of sperm cells, could be influenced, at least partially, by histoincompatibility. Outbred Hartley and inbred strain 13 guinea pigs were alloimmunized with sperm cells emulsified in Freund's complete adjuvant. The degree of histocompatibility between recipients and sperm cell donors was determined by using mixed lymphocyte culture assays. Stimulatory indices higher than four, indicating histoincompatibility, were obtained frequently between members of Hartley strain or between Hartley and strain 13 guinea pigs, but never between strain 13 animals. Sperm cells from histoincompatible guinea pigs failed to stimulate blastogenesis in lymphoid cells from nonimmunized animals. The lymphoblastogenic potential of allo‐ and isospermatozoa were compared. Lymphoid cells from Hartley and strain 13 guinea pigs alloimmunized with sperm cells were incubated in vitro with histocompatible and histoincompatible sperm cells. Both strain 13 and Hartley sperm cells gave a similar stimulatory index with lymphoid cells belonging to outbred or inbred alloimmunized guinea pigs. The use of fresh spermatozoa was of paramount importance. Frozen specimens lost their stimulatory capacity almost completely. Within the limits of the technique utilized here, we have failed to detect any influence of the antigens coded by the major histocompatibility complex of the guinea pig upon the sperm‐induced lymphocyte transformation. These observations point to the sperm‐specific autoantigens as being responsible for the lymphocyte pr