The incidence of pregnancy loss is higher in patients with various autoimmune diseases than in the general population. The causes of recurrent spontaneous abortions (RSA) are unknown; however, the presence of antinuclear antibodies and other antibodies in some women with RSA who are otherwise healthy suggests the possibility of underlying autoimmune disease. Because autoimmune diseases are often associated with an increased incidence of certain histocompatibility antigens, we examined the occurrence of specific HLA antigens in patients who had been treated for RSA. We found HLA-DR5 to be significantly overrepresented in the patients with RSA who aborted again after treatment with paternal mononuclear cell immunotherapy, compared with the incidence of this phenotype in a control population. Neither antinuclear antibodies nor antilymphocyte antibodies segregated with DR5. However, DR5+ patients who developed antilymphocyte antibodies after immunotherapy were more likely than all other treated patients to experience subsequent abortion (P less than 0.01). Our findings suggest the possibility of an underlying autoimmune disease in these women.