BACKGROUND: Future U.S. congressional funding for the President's Emergency Plan for AIDS Relief (PEPFAR) program is uncertain. OBJECTIVE: To evaluate the clinical and economic impacts of abruptly scaling back PEPFAR funding ($460 million) from South Africa's total HIV budget ($2.56 billion) in 2024. DESIGN: Model-based analysis of 100%, 50%, and 0% PEPFAR funding with proportional decreases in HIV diagnosis rates (26.0, 24.3, 22.6 per 100 person-years [PY]), 1-year treatment engagement (people with HIV [PWH] receiving/initiating antiretroviral therapy: 92.2%/80.4%, 87.1%/76.0%, 82.0%/71.5%), and primary prevention (4.0%, 2.2%, 0.5% reduction in incidence with no programming [1.24 per 100 PY]). DATA SOURCES: Published HIV care continuum; PEPFAR funding estimates. TARGET POPULATION: South African adults (HIV prevalence, 16.2%; incidence, 0.32 per 100 PY). TIME HORIZON: Lifetime. PERSPECTIVE: Health care sector. INTERVENTION: PEPFAR funded 100% (PEPFAR_100%), 50% (PEPFAR_50%), or 0% (PEPFAR_0%). OUTCOME MEASURES: HIV infections, life expectancy, and lifetime costs (2023 U.S. dollars). RESULTS OF BASE-CASE ANALYSIS: With current HIV programming (PEPFAR_100%), 1 190 000 new infections are projected over 10 years; life expectancy would be 61.42 years for PWH, with lifetime costs of $11 180 per PWH. Reduced PEPFAR funding (PEPFAR_50% and PEPFAR_0%) would add 286 000 and 565 000 new infections, respectively. PWH would lose 2.02 and 3.71 life-years with nominal lifetime cost reductions of $620 per PWH and $1140 per PWH that would be offset at the population level by more PWH requiring treatment for infection. RESULTS OF SENSITIVITY ANALYSIS: Countries with similar HIV prevalence and greater reliance on PEPFAR funding could experience disproportionately higher incremental infections and survival losses. LIMITATION: Budget fungibility and exact programmatic implications of reducing PEPFAR funding are unknown. CONCLUSION: Abrupt PEPFAR cutbacks would have immediate and long-term detrimental effects on epidemiologic and clinical HIV outcomes in South Africa. PRIMARY FUNDING SOURCE: National Institutes of Health.