The extent to which maternal anti-Rh(D) antibodies support lysis of erythrocytes by monocytes in the antibody-dependent cell-mediated cytotoxicity (ADCC) assay is closely correlated with the severity of Rh(D) haemolytic disease of the newborn infant (HDN). However, in some cases HDN is much milder than would be predicted from the ADCC value. We postulated that maternal ADCC-blocking alloantibodies against paternal antigens on monocytes can protect these infants against severe haemolysis. We studied 13 severely Rh(D)-alloimmunised mothers whose infants showed unexpectedly mild HDN (group I) and 14 women with similar ADCC values but whose infants had severe HDN (group II). 7 group-I women had monocyte-reactive IgG alloantibodies that inhibited lysis by paternal monocytes in the ADCC. No such antibodies were found in group II (p less than 0.01). In 6 of the 7 serum samples with monocyte-reactive antibodies, the antibodies had HLA-DR specificity. Our findings suggest that Rh(D)-positive children of some severely Rh(D)-alloimmunised women may be protected from severe HDN by maternal non-HLA-class-I, IgG alloantibodies against paternal monocyte blood-group antigens. These antibodies may inhibit the mononuclear phagocyte system of the fetus.