OBJECTIVES: Artemisinin combination based therapy (ACT) was started in Ghana in 2002 as a result of failure of monotherapy in the treatment of falciparum malaria. The decision to change was in line with recommendations from the World Health Organisation. ArtesunateAmodiaquine (A-Q) is the preferred combination drug of choice for the treatment of uncomplicated malaria and Artemether-Lumefantrine (A-L) is an alternative first line option. This study evaluates the cost-effectiveness of A-Q compared with A-L among under-five year olds in Ghana. METHODS: In this study a decision analytic model using a decision tree was developed to assess the cost-effectiveness of the two treatments. Cost of illness and cost of medication (Coartem paediatric and Camoquine plus) were determined using figures from the National Health Insurance Scheme (NHIS) Ghana and from wholesalers respectively. Transportation cost was estimated using exit interviews. With the help of randomized controlled trials we estimated malaria cases averted (using clinical failure rates) over a 28 day period post treatment with each drug. Costs were discounted by 3% over a five year period but malaria cases averted 28 days after treatment was not discounted. Incremental costs per uncomplicated malaria case averted was then determined. RESULTS: The cost of illness per episode of uncomplicated malaria was 7.50 Ghana cedis (bundled NHIS cost) and transportation cost was 3.00 Ghana cedis. The incremental cost effectiveness ratio of artesunate-amodiaquine compared with artemether-lumefantrine was 16 Ghana cedis per uncomplicated malaria case averted CONCLUSIONS: This economic evaluation showed that in the Ghanaian setting, treating uncomplicated malaria in under-five year old children with artesunate-amodiaquine was more cost-effective compared with artemether-lumefantrine.