CXCR6 genetic variation was described for HIV-1-uninfected black (n = 41) and Caucasian (n = 40) South Africans. We also investigated the CXCR6 rs2234358 and rs2234355 single nucleotide polymorphisms in HIV-1 disease control in 124 HIV-1-infected drug-naïve black individuals [elite controllers (n = 11), viraemic controllers (VCs, n = 30), high viral load long-term nonprogressors (HVL LTNPs, n = 11) and progressors (n = 72)] compared to healthy controls (HCs; n = 232). The rs2234358-T allele was underrepresented in VCs (40.0%) compared to HCs (59%, P = 0.006), HVL LTNPs (72.7%, P = 0.012) and progressors (59%, P = 0.014). The rs2234358-TT genotype was underrepresented in VCs (7%) compared to progressors (32%; OR = 6.57, P = 0.006) and HCs (35%; OR = 7.18, P = 0.001, Pbonferroni = 0.034). The rs2234355-GA genotype was overrepresented in VCs (80%) compared to HCs (50.4%; OR = 0.25, P = 0.003) and progressors (29.17%; OR = 0.10, P = 3.8 × 10- 5, Pbonferroni = 0.001). The combination of rs2234355-GA in the absence of rs2234358-TT was overrepresented in VCs (80%) compared to HCs (32.6%, OR = 0.12, P = 1 × 10- 6, Pbonferroni = 3.4 × 10- 5) and to progressors (16.7%; OR = 0.05, P < 1 × 10- 8, Pbonferroni < 1 × 10- 7).