ABSTRACT: Previous observations have suggested that defective recognition of fetal alloantigens by the maternal immune system is associated with recurrent pregnancy failure and that this may be prevented by boosting the maternal immune system with paternal or pooled third-party leukocytes. The mechanism whereby this process achieves success is not clear, and accordingly to explore this we immunized 28 couples with recurrent fetal loss with 80 × 106 paternal peripheral blood mononuclear leukocytes (PBML) and followed various immunological parameters. The couples studied, in whom 55% achieved a successful pregnancy, showed no increase in sharing of human lymphocyte antigen (HLA)-A, -B, or -DR antigens and no consistent evidence of a decreased mixed leukocyte reaction (MLR) or MLR plasma-blocking factors compared with control couples. Immunization did not alter these parameters but did induce antipaternal lymphocytotoxins, although the presence of the latter did not correlate with pregnancy outcome. There was a correlation between rapid conception after immunization and a subsequent successful pregnancy. A successful pregnancy also correlated with sustained postimmunization, postconception maternal antipaternal allospecific CD-8+ suppressor T cells. Although these findings provide overall evidence that immunization produces changes in the way in which the maternal immune system interacts with the fetus, larger numbers of couples and a higher dose of paternal lymphocytes will be needed to establish clearly whether this therapy works and its mechanism of action.