OBJECTIVES: The study evaluated the cost-effectiveness of commonly used ACT regimens for the treatment of uncomplicated malaria, to inform policy on the efficiency of malaria treatment in Nigeria METHODS: From a provider’s perspective, the relative costs and effects of commonly used ACTs; AL, DHAPQ, ASSP and ASAQ compared to SP were evaluated to determine their efficiency in the treatment of uncomplicated malaria, from a routine hospital setting. Cost and effect data were collected from patients who presented at the OPD of a public health facility with uncomplicated malaria, and were randomized to a three-day course of treatment with each regimen. Effects data was based on the efficacy and compliance to treatment. Cost data was based on the direct costs of recurrent and capital inputs such as drugs, labour, operation, equipment and building. Drug costs were based on their dosages and unit prices collected from the manufacturers of the key brands. Efficacy outcomes were measured at days 14 and 28 after initiation of treatment. Results were presented as incremental cost-effectiveness ratio (ICER). RESULTS: The ICERs ranged between $4.10 (DHAPQ) and 6.73 (ASSP) per additional malaria case treated. Further analysis showed that DHAPQ generated the least cost per additional malaria case treated, dominating other ACTs as the most cost-effective agent. Diagnostic accuracy, cost of drugs and compliance to treatment were the key parameters that significantly influenced the cost-effectiveness results, without changing the order of magnitude. CONCLUSIONS: Dihydro-artemisinin-piperaquine at a given budget is the most cost-effective regimen for treating uncomplicated malaria, generating the most cost-savings and greatest number of malaria treatments, compared to other agents. This should inform policy on the choice of first line drug for improved efficiency of malaria treatment in Nigeria