Background: Viral load (VL) testing is recommended for monitoring people living with HIV on antiretroviral therapy (ART). The National Health Laboratory Service (NHLS) in South Africa conducted >5 million VL tests at 16 laboratories in 2018 but faced challenges with specimen integrity and results delivery. Point-of-care (POC) VL monitoring may improve results delivery and viral suppression. We assessed the cost-effectiveness of different adoption strategies for POC testing in South Africa. Methods: We developed a cost-outcome model utilizing NHLS data, including facility-level annual VL volume, suppression rates (<1000 copies/ml), specimen rejection rates, turn-around time, and the cost/test. We assessed the health and economic impact of adopting two validated POC VL technologies (Cepheid GeneXpert and Abbott m-PIMATM) under 4 scenarios: 1) status-quo; 2) targeted POC testing at facilities with high levels of viral failure; 3) targeted POC testing at low-performing facilities; and 4) complete POC adoption. For each scenario, we determined the total cost, effectiveness (expected number of people with suppressed VL) and incremental cost-effectiveness ratio (ICER) based on expected improvement in suppression rates. Finding: The existing centralized network of laboratory based VL testing costs $126m annually and achieves a VL suppression rate of 85.2%. Targeted testing using the GeneXpert, was the most cost-effective approach, with 88.5% VL suppression and $40 per additional person suppressed, compared to the centralized network. Should resources allow, complete POC VL adoption may be cost-effective (ICER: $136/additional person suppressed), requiring an additional $49m annually and achieving VL 94.5% suppression. All other scenarios were dominated in the incremental analysis. Interpretation: Assuming POC HIV viral load monitoring confers clinical benefits consistent with trial results, the most cost-effective strategy for POC adoption in South Africa is likely a targeted approach with POC VL technologies placed at facilities with high rates of viral failure.