Background: In line with the recommendation of artemisininbased combination therapy (ACT) by WHO in the effective treatment of uncomplicated malaria, African nations including Nigeria changed their malaria treatment policy to combination therapies. To date, about 15 African nations adopted artesunate /amodiaquine (AA) as their first line agent while Nigeria adopted artemether /lumefantrine (AL). Objective: The objective of this study is to compare the treatment outcome among patients treated with AA to those treated with AL for acute uncomplicated malaria. Method: The study was conducted at Nnamdi Azikiwe University campuses using quantitative methods. Two hundered and ninety six patients were randomly allocated to one of two treatment group- AA and AL with 148 patients per group. All the patients were educated about the drugs and adherence. Adherence and treatment outcomes including parasite clearance and the drugs’ effects on biochemical parameters among others were assessed by follow up visits on third, seventh, fourteenth and twenty eighth-day post treatment. Data were analysed using Cox Regression model on SPSS 17.0. Result: Both drugs were well adhered to and tolerated. One case of Steven Johnson-like reaction was observed with AL. Fever resolution and parasite clearance was similar in both groups with adequate clinical and parasitological response (ACPR) by day 28 for AL and AA being 70.3% and 85.1% respectively. Conclusion: Our findings is in favour of higher efficacy of AA with respect to their ACPR. More controlled studies will be needed to ascertain the adoption of AL as first line drug in malaria treatment in Nigeria.