© 2017 American Society for Histocompatibility and Immunogenetics Immune control of HIV-1 infection depends heavily on cytotoxic T-lymphocyte responses restricted by diverse HLA class I molecules. Recent work has uncovered specific amino acid residues (AARs) that seem to dictate the extent of immune control in African Americans, which prompted us to test these emerging hypotheses in seroconverters (SCs) from southern and eastern Africa. Based on data from 196 Zambians and 76 Rwandans with fully resolved HLA alleles and pre-therapy HIV-1 viral loads (VL) in the first 3- to 36-month of infection (>2300 person-visits), four AARs of primary interest (positions 63, 97, 116 and 245 in the mature HLA-B protein) were found to explain 8.1% and 15.8% of variance in set-point VL for these cohorts (P =.024 and 7.5 × 10−6, respectively). Two AARs not reported previously (167S in HLA-B and 116F in HLA-C) also showed relatively consistent associations with VL (adjusted P =.009–.069), while many population-specific associations were also noted (false discovery rate <0.05). Extensive and often strong linkage disequilibrium among neighboring AAR variants called for more extensive analyses of AAR haplotypes in diverse cohorts before the structural basis of antigen presentation can be fully comprehended.