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In 2015, the WHO recommended initiation of antiretroviral therapy (ART) in all HIV-positive patients regardless of CD4+ cell count. We evaluated the cost-effectiveness of immediate versus deferred ART initiation among patients with CD4+ cell counts exceeding 500cells/μl in four resource-limited countries (South Africa, Nigeria, Uganda, and India).A 5-year Markov model with annual cycles, including patients at CD4+ cell counts more than 500 cells/μl initiating ART or deferring therapy until historic ART initiation criteria of CD4+ cell counts more than 350 cells/μl were met.The incidence of opportunistic infections, malignancies, cardiovascular disease, unscheduled hospitalizations, and death, were informed by the START trial results. Risk of HIV transmission was obtained from a systematic review. Disability weights were based on published literature. Cost inputs were inflated to 2014 US dollars and based on local sources. Results were expressed in cost per disability-adjusted life years averted and measured against WHO cost-effectiveness thresholds.Immediate initiation of ART is associated with a cost per disability-adjusted life years averted of −$317 [95% confidence interval (CI): −$796–$817] in South Africa; −$507 (95% CI: −$765–$837) in Nigeria; −$136 (−$382–$459) in Uganda; and −$78 (−$256–$374) in India. The results are largely driven by the impact of ART on reducing the risk of new HIV transmissions.In HIV-positive patients with CD4+ counts above 500 cells/μl in the four studied countries, immediate initiation of ART versus deferred therapy until historic eligibility criteria are met is cost-effective and likely even cost-saving over time.