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Objectives Cryptococcal meningitis (CM)-related mortality may be prevented by screening patients for sub-clinical cryptococcal antigenaemia (CRAG) at antiretroviral-therapy (ART) initiation and pre-emptively treating those testing positive. Prior to programmatic implementation in South Africa we performed a cost-effectiveness analysis of alternative preventive strategies for CM. Design Cost-effectiveness analysis. Methods Using South African data we modelled the cost-effectiveness of four strategies for patients with CD4 cell-counts< 100 cells/µl starting ART 1) no screening or prophylaxis (standard of care), 2) universal primary fluconazole prophylaxis, 3) CRAG screening with fluconazole treatment if antigen-positive, 4) CRAG screening with lumbar puncture if antigen-positive and either amphotericin-B for those with CNS disease or fluconazole for those without. Analysis was limited to the first year of ART. Results The least costly strategy was CRAG screening followed by high-dose fluconazole treatment of all CRAG-positive individuals. This strategy dominated the standard of care at CRAG prevalence≥ 0.6%. Although CRAG screening followed by lumbar puncture in all antigen-positive individuals was the most effective strategy clinically, the incremental benefit of LPs and amphotericin therapy for those with CNS disease was small and additional costs were large (US 158versusUS 51 per person year; incremental cost effectiveness ratio (ICER) US 889,267perlifeyeargained).BothCRAGscreeningstrategiesarelesscostlyandmoreclinicallyeffectivethancurrentpractice.Primaryprophylaxisismoreeffectivethancurrentpractice,butrelativelycost …