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To examine the clinical and economic value of point-of-care CD4+ (POC-CD4+) or viral load monitoring compared with current practices in Mozambique, a country representative of the diverse resource limitations encountered by HIV treatment programs in sub-Saharan Africa.We use the Cost-Effectiveness of Preventing AIDS Complications-International model to examine the clinical impact, cost (2014 US$), and incremental cost-effectiveness ratio [$/year of life saved (YLS)] of ART monitoring strategies in Mozambique. We compare: monitoring for clinical disease progression [clinical ART monitoring strategy (CLIN)] vs. annual POC-CD4+ in rural settings without laboratory services and biannual laboratory CD4+ (LAB-CD4+), biannual POC-CD4+, and annual viral load in urban settings with laboratory services. We examine the impact of a range of values in sensitivity analyses, using Mozambique's 2014 per capita gross domestic product ($620) as a benchmark cost-effectiveness threshold.In rural settings, annual POC-CD4+ compared to CLIN improves life expectancy by 2.8 years, reduces time on failed ART by 0.6 years, and yields an incremental cost-effectiveness ratio of $480/YLS. In urban settings, biannual POC-CD4+ is more expensive and less effective than viral load. Compared to biannual LAB-CD4+, viral load improves life expectancy by 0.6 years, reduces time on failed ART by 1.0 year, and is cost-effective ($440/YLS).In rural settings, annual POC-CD4+ improves clinical outcomes and is cost-effective compared to CLIN. In urban settings, viral load has the greatest clinical benefit and is cost-effective compared to biannual POC-CD4+ or LAB-CD4+. Tailoring ART monitoring strategies to specific settings with different available resources can improve clinical outcomes while remaining economically efficient.