BACKGROUND: In response to increasing resistance to non-nucleoside reverse transcriptase inhibitors, millions of people living with HIV have switched to dolutegravir-based antiretroviral therapy, so understanding the possible emergence of dolutegravir resistance is essential. We aimed to predict how dolutegravir resistance in South Africa will change over time. METHODS: For this modelling study, we used the Modelling Antiretroviral Drug Resistance in South Africa (MARISA) model, a deterministic compartmental model calibrated to reproduce the HIV-1 epidemic in South Africa from 2005 to 2035 using data from the International Epidemiology Databases to Evaluate AIDS collaboration and the literature. Key parameters for modelling dolutegravir-resistance evolution were acquisition rates of dolutegravir-resistance mutations, reversion rates of dolutegravir-resistance mutations, the effect of resistance to nucleoside reverse transcriptase inhibitors on dolutegravir-resistance acquisition, the effect of dolutegravir resistance on dolutegravir-treatment efficacy, the probability of transmitting dolutegravir drug-resistance mutations compared with the probability of transmitting wild-type HIV, and the proportion of people with virologic failure on dolutegravir-based antiretroviral therapy with detectable drug levels. Model outcomes were estimated transmitted dolutegravir resistance and estimated acquired dolutegravir resistance. FINDINGS: We estimated a substantial increase in the number of individuals on dolutegravir-based antiretroviral therapy after its introduction in 2020, increasing from 0 to approximately 7 million people (7·08-7·15) living with HIV on dolutegravir in 2035. We estimated the proportion of people living with HIV with viral suppression (ie, viral load <1000 copies per mL) on dolutegravir-based antiretroviral therapy to be 93% (uncertainty range 92·2-94·3) in 2035. We estimated that acquired dolutegravir resistance in people living with HIV on failing dolutegravir-based antiretroviral therapy would increase rapidly, from 18·5% (uncertainty range 12·5-25·4) in 2023 to 41·7% (29·0-54·0) in 2035. For transmitted dolutegravir resistance, we estimated an increase from 0·1% (0·0-0·2) in 2023 to 5·0% (1·9-11·9) in 2035. We estimated that resistance-mitigation strategies involving rapid switching to protease-inhibitor-based antiretroviral therapy could effectively reduce the increase in acquired dolutegravir resistance and slow the increase in transmitted dolutegravir resistance. INTERPRETATION: Although dolutegravir-based antiretroviral therapy maintains high virological suppression, acquired and transmitted dolutegravir resistance are likely to increase. This increase will likely be greater in settings where HIV RNA monitoring, genotypic-resistance testing, and options to switch antiretroviral therapy regimens are scarce. FUNDING: US National Institutes of Health National Institute of Allergy and Infectious Diseases, Swiss National Science Foundation, and University of Zurich Research Priority Program Evolution in Action.< Réduire