ObjectiveRenal toxicity is more common with tenofovir disoproxil fumarate (TDF) than with tenofovir alafenamide fumarate (TAF). We investigated whether polymorphisms in genes relevant to tenofovir disposition affect renal toxicity among HIV-positive Southern Africans.MethodsGenetic sub-study of adults randomized to initiate TAF or TDF together with dolutegravir and emtricitabine was conducted. Outcomes were changes from week 4 to 48 in the estimated glomerular filtration rate (eGFR) and from baseline to week 48 in urine retinol-binding protein and urine β2-microglobulin adjusted for urinary creatinine (uRBP/Cr and uB2M/Cr). Primary analyses prioritized 14 polymorphisms previously reported to be associated with tenofovir disposition or renal outcomes, and all polymorphisms in 14 selected genes. We also explored genome-wide associations.Results336 participants were enrolled. Among 14 polymorphisms of primary interest, the lowestPvalues for change in eGFR, uRBP/Cr, and uB2M/Cr wereABCC4rs899494 (P= 0.022),ABCC10rs2125739 (P= 0.07), andABCC4rs1059751 (P= 0.0088); and in genes of interest, the lowestPvalues wereABCC4rs4148481 (P= 0.0013), rs691857 (P= 0.00039), andPKD2rs72659631 (P= 0.0011). However, none of these polymorphisms withstood correction for multiple testing. Genome-wide, the lowestPvalues wereCOL27A1rs1687402 (P= 3.4 × 10−9),CDH4rs66494466 (P= 5.6 × 10−8), andITGA4rs3770126 (P= 6.1 × 10−7).ConclusionTwoABCC4polymorphisms, rs899494 and rs1059751, were nominally associated with change in eGFR and uB2M/Cr, respectively, albeit in the opposite direction of previous reports.COL27A1polymorphism was genome-wide significantly associated with change in eGFR.