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Background. Optimal laboratory monitoring of antiretroviral therapy (ART) for human immunodeficiency virus (HIV) remains controversial. We evaluated current and novel monitoring strategies in Côte d′Ivoire, West Africa.Methods. We used the Cost-Effectiveness of Preventing AIDS Complications –International model to compare clinical outcomes, cost-effectiveness, and budget impact of 11 ART monitoring strategies varying by type (CD4 and/or viral load [VL]) and frequency. We included “adaptive” strategies (biannual then annual monitoring for patients on ART/suppressed). Mean CD4 count at ART initiation was 154/μL. Laboratory test costs were CD4=$11 and VL=$33. The standard of care (SOC; biannual CD4) was the comparator. We assessed cost-effectiveness relative to Côte d′Ivoire's 2013 per capita GDP ($1500).Results. Discounted life expectancy was 16.69 years for SOC, 16.97 years with VL confirmation of immunologic failure, and 17.25 years for adaptive VL. Mean time on failed first-line ART was 3.7 years for SOC and <0.9 years for all routine/adaptive VL strategies. VL failure confirmation was cost-saving compared with SOC. Adaptive VL had an incremental cost-effectiveness ratio (ICER) of $4100/year of life saved compared with VL confirmation and increased the 5-year budget by $310/patient compared with SOC. Adaptive VL achieved an ICER <1× GDP if second-line ART and VL costs simultaneously decreased to $156 and $13, respectively.Conclusions. VL confirmation of immunologic failure is more effective and less costly than CD4 monitoring in Côte d′Ivoire. Adaptive VL monitoring reduces time on failing ART, is cost-effective, and should become standard in Côte d′Ivoire and similar settings.