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One hundred sixty-one couples with clinical histories of unexplained recurrent spontaneous abortions were analyzed in part for human leukocyte antigens, antibodies to paternal lymphocytes, and mixed lymphocyte culture reactions. All sera with antipaternal antibodies were investigated on a cell panel and absorbed with various tissues and heparin to help define antigenic specificities, and the couples were categorized as primary or secondary aborters. Primary but not secondary aborters were found to share more human leukocyte antigens with their mates than did 103 control fertile couples. Lymphocytotoxins were rarely identified in primary but were commonly present in secondary aborter sera. Results of mixed lymphocyte culture reactions with primary aborting couples showed an intrinsic cellular inability for the wives to recognize their husbands' cells. Secondary aborting couples' mixed lymphocyte culture reactions also were depressed but as a result of an inhibiting substance in the wives' sera. Thirty-three primary aborting women were treated by immunotherapy with leukocyte infusions as a prophylactic source of trophoblast-lymphocyte cross reactive antigen stimulation to immunologically protect their pregnancies. Eighty-nine percent of primary aborting patients delivered successfully. Six secondary aborting women were treated with heparin therapy; two of these delivered normal infants, two are pregnant, and two have aborted. Clinical implications for immunologic testing and immunotherapy in pregnancy failures are discussed.