Background: Excessive weight gain affects some HIV-positive individuals prescribed dolutegravir-containing regimens. Mechanisms underlying such weight gain are unknown., Setting: Data and DNA from antiretroviral therapy-naïve participants who were randomized to initiate dolutegravir with emtricitabine plus either tenofovir alafenamide (TAF) or tenofovir disoproxil fumarate (TDF) in the ADVANCE study (NCT03122262) were used to characterize associations between human genetic polymorphisms and magnitude of weight gain., Methods: Associations with percent weight gain from baseline to week 48 were assessed using multivariable linear regression models. Primary analyses a priori considered 59 polymorphisms and 10 genes of potential relevance to dolutegravir, TAF, or TDF pharmacokinetics. We also explored genome-wide associations., Results: Among the 314 (92%) of 340 dolutegravir recipients who were successfully genotyped, 160 (47%) and 154 (45%) were randomized to TAF/emtricitabine and TDF/emtricitabine, respectively. In target gene analyses, the lowest P-values for the dolutegravir and tenofovir groups were ABCG2 rs4148149 (P = 7.0 × 10-4) and ABCC10 rs67861980 (P = 1.0 × 10-2), respectively, which were not significant after correction for multiple testing. In genome-wide analyses, the lowest P-values were rs7590091 in TMEM163 (P = 3.7 × 10-8) for dolutegravir, rs17137701 in LOC105379130 (P = 6.4 × 10-8) for TAF, and rs76771105 in LOC105371716 (P = 9.7 × 10-8) for TDF., Conclusions: Among South African participants in a randomized clinical trial of dolutegravir plus either TAF/emtricitabine or TDF/emtricitabine, we identified several potential genetic associations with weight gain. Only TMEM163 rs7590091 withstood correction for multiple testing. These associations warrant replication in other cohorts., Competing Interests: Research reported in this publication was supported by the Fogarty International Center (FIC) of the National Institutes of Health (NIH) under Award Number D43 TW010559 and National Heart, Lung, And Blood Institute of the NIH and the FIC, under Award Number UG3HL156388. Furthermore, this work was supported by National Research Foundation through the Thuthuka Grant [113983] and Black Academic Advancement Program Grant [120647], the South African Medical Research Council (SAMRC) through self-initiated research grant (P.S.), the Wellcome Trust (WT) through an investigator award [212265/Z/18/Z], the National Research Foundation (NRF) of South Africa (Grant Number 119078), and core funding for the Wellcome Centre for Infectious Diseases Research in Africa [203135/Z/16/Z] (G.M.). Grant support included TW010559, AI110527, AI077505, TR000445, and AI110527 (D.W.H.). Gilead Sciences and ViiV Healthcare donated study drugs for the conduct of the parent study. F. Venter reports grants from USAID, Unitaid, SAMRC, and ViiV; personal fees and nonfinancial support from ViiV Healthcare and Gilead Sciences, during the conduct of the study; and personal fees from Mylan, Merck, Adcock-Ingram, Aspen, Abbott, Roche, and Johnson and Johnson, outside the submitted work. SS reports grants from USAID, Unitaid, SAMRC, and ViiV Healthcare during the conduct of the study. N. Chandiwana reports personal fees and nonfinancial support from Johnson and Johnson, grants from USAID, Unitaid, SAMRC, and ViiV Healthcare during the conduct of the study. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH, WT, NRF, SAMRC, or other funders. The remaining authors have no funding or conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)