Background: Integrase inhibitors, including dolutegravir, may increase risk of major adverse cardiovascular events (MACEs). However, limited data exists from low- and middle-income countries, where tenofovir disoproxil fumarate, lamivudine, and dolutegravir (TLD) has largely replaced tenofovir disoproxil fumarate, emtricitabine, and efavirenz (TEE). Methods: We used de-identified data from a South African managed healthcare organization from people with HIV (PWH) without cardiovascular disease, who either initiated TEE or TLD between April 2020 and Dec 2023 (initiation cohort) or were receiving TEE in April 2020 and eligible for TLD (transition cohort). In the initiation cohort, we emulated a target trial using pooled logistic regression models with inverse probability of treatment weights and bootstrapped CIs to compare estimated 3-year MACE risk between TLD versus TEE. In the transition cohort, we used similar methods in 44 emulated monthly sequential trials, comparing MACE risk in people transitioned to TLD with those remaining on TEE. Results: In the initiation cohort, 7310 PWH initiated TLD (n = 3711) or TEE (n = 3599). Median follow-up was 21 months (IQR 10–33), with 18 MACEs with TLD (3-year risk 0.78%, 95% CI .38–1.11) and 28 with TEE (3-year risk 1.03%, 0.63–1.55; RR 0.75, 0.31–1.30; RD −0.25, −0.94–0.24). In the transition cohort, 22 338 people contributed to 2837 person-trials with TLD and 706 615 with TEE. Median follow-up was 25 months (14–36), with 19 MACEs with TLD (3-year risk 0.97%, 0.52–1.62) and 5420 with TEE (3-year risk 1.17%, 0.99–1.37; RR 0.83, 0.45–1.39; RD −0.20, −0.66–0.44). Conclusions: Among PWH in South Africa, we found no increased MACE with TLD.