Mild courses of haemolytic disease of the foetus or newborn (HDN) due to Rh (D) blood group antibodies are associated with and may therefore be ameliorated by maternal antibodies reacting with human leucocyte antigens (HLA) of the child, an observation drawn from our own earlier data (Neppert J, Kissel K. Lancet 1992;339:1481). This study (i) corroborates this association; (ii) reveals shortcomings in the published data; and (iii) examines the characteristics of HDN cases when these shortcomings have been rectified. Samples from 51 women with antibodies against their child's blood group antigens of the Rh system were analysed for HLA A, B, C and DR antibodies during parturition. The mothers were divided into two groups, either severe or mild, dependent upon the clinical course of the HDN, and the incidence of HLA antibody production was determined for each group. HLA A, B, C and/or DR antibodies were detected in 85.2% of those women whose children had a mild course of HDN prenatally or perinatally (n=27). This is statistically greater than the incidence of 50.0% (Fisher's exact test: p=0.014) found in the group of women whose children had a severe HDN either pre- or perinatally (n=24) and is greater than the 35% (n=20; p=0.0001) found in women without Rh or other irregular antibodies. HLA DR antibodies were detected in three cases. The findings support our hypothesis that maternal anti HLA A, B and C antibodies may protect against a potential severe HDN. We therefore assume that those women will benefit who have already had a child with a severe HDN and in whom HLA antibodies were not previously detected, if HLA antibody production is provoked by subcutaneously inoculating with the father's leucocytes before or at the beginning of the new pregnancy.