This study evaluates genetic influence on susceptibility to perinatal HIV-1 infection among 106 Black infants from New York and San Francisco born to mothers infected with HIV-1. Genes tested by molecular techniques are HLA class II loci DRB1, DPB1 and DQA1; HLA class III loci complement C4A and C4B; alpha and beta interferons; and the constant region of the T-cell receptor beta chain. Of the 106 infants analysed, 54 are infected with HIV and 52 remain uninfected at age 15 months and older. Genotypes in the HLA region appear to influence risk of HIV infection. Specifically, infants with the amino acid sequence -asp-glu-ala-val- at DPB1 positions #84-87 are more likely to be infected (P = 0.001) and infants with the allele DQA1*0102 are less likely to be infected (P = 0.031). Combinations of these two risk factors show a strong dose response (P = 0.0005). HLA DPB1 and DQA1 may play a direct role in immune response associated with HIV-1 infection, or the critical region may be located between these two genes. Characterisation of other class II HLA genes in these infants will allow more precise determination of the role of HLA loci in susceptibility to HIV-1 infection.