The laboratory diagnosis and clinical management of unexplained recurrent spontaneous abortion (RSA) patients is a controversial issue in contemporary obstetrics. In this report, the results of laboratory investigations and immunotherapy of RSA patients referred to our Center since 1986 are detailed. Our analyses have resulted in grouping RSA patients into primary (1 degree), secondary (2 degrees), and unexplained classifications. Laboratory evaluation criteria included assays for both complement-dependent and complement-independent antipaternal antibodies as well as histocompatibility antigen tissue typing for HLA, A, B, C, and DR antigens. In addition, mixed lymphocyte cultures (MLC) were performed to assess the degree of HLA-D locus compatibility between couples and to test for the presence of MLC inhibitors in maternal blood. Immunotherapy options and the rationale for their use are given and preliminary outcome data are presented from randomized double-blinded, placebo-controlled clinical trials.