Infection with human immunodeficiency virus type 1 (HIV-1) and progression to acquired immune deficiency syndrome (AIDS) are controlled by both host genetic factors and viral factors. The HLA (human leukocyte antigen) region in humans controls immune response functions and tissue rejection and influences susceptibility to neoplasia, autoimmune diseases, and infectious diseases including HIV. Twenty-eight African American and 12 Caucasian patients participated in the study. HLA-DQB1 and HLA-DRB1 genotyping was performed using PCR and sequence-specific oligonucleotide probe reverse hybridization and analyzed with the LiPA Key Typing System and LiPA software. DQB1*0603 was found to be positively associated with HIV-1 infection and with HIV-1 infection in Caucasians but not African Americans. DQB1*03032 frequencies indicate a positive association with protection from HIV-1 infection. It was further found to be protective against HIV-1 infection in Caucasians but not in African Amens. DQB1*0201 was observed more frequently in HIV(+) African Americans than HIV(-) African Americans, suggesting a positive association with HIV-1 infection in this ethnic group. HLA-DRB1*04 exhibited a positive association with HIV-1 infection in Caucasians. These data show that there are HLA class II alleles associated with susceptibility to and protection from HIV-1 infection and that these differ between ethnic groups.