Abstract Background and Aims Apolipoprotein 1 (APOL1) renal allelic risk variants are common in kidney disease patients of African ancestry. This study evaluated the prevalence of APOL1 variants and their influence on end-stage kidney failure (ESKD) and non-ESKD HIV-positive and HIV-negative study cohorts. Method This case‒control study enrolled 60 HIV-positive ESKD cases and 160 non-ESKD (80 HIV-positive and 80 HIV-negative) as controls. Participants’ demographic and clinical information and laboratory data as well as blood samples were collected. Genomic DNA was extracted, and purified, and APOL1 risk variants genotyped using TaqMan® predesigned commercial assays. Results Study participants in the case and two control cohorts were enrolled with a median age of 42.8 (IQR,38.47-48.57), 41 (IQR,37-46.5), and 41 (IQR,37–47) years, respectively; the frequencies of APOL1 risk variants (G1: rs73885319 and rs60910145 and G2: rs71785313) were 21.8% (48/220), 10.9% (24/220), and 26.4% (58/220), respectively, in the entire study population. The frequency of G1 variants was significantly increased among those with ESKD at 55.0% (33/60) compared to non-ESKD HIV-positive and HIV-negative cohorts at 13.8% (11/80) and 17.5% (14/80), respectively (p < 0.001). The presence of both G1 risk genotypes (rs73885319 and rs60910145) was higher among those with ESKD at 20% (12/60) compared to the two control cohorts without ESKD at rates of 3.8% (3/80) and 1.3% (1/80), respectively (p < 0.001). In logistic regression, the presence of both G1 (OR,14.6; p ≤ 0.001) and G1/G2 (OR,11.9; p ≤ 0.001) risk genotypes were strong predictors of ESKD development. Conclusion The presence of G1:rs73885319 and rs60910145 polymorphisms of the APOL1 gene is suggested to be a significant factor in the development of ESKD.