Background: Rectal artesunate has been shown to be an effective treatment for falciparum malaria and is useful in patients who cannot take medicine orally or when parenteral medication is inconvenient. A combination with mefloquine can decrease the duration of treatment, increase compliance and delay development of resistance. There are no clear data on whether a higher dosage of rectal artesunate results in a better clinical response. Aim: To assess two rectal artesunate/oral mefloquine regimens for treating uncomplicated multi-drug-resistant childhood falciparum malaria. Methods: Seventy children aged 1–14 years with uncomplicated falciparum malaria were randomly assigned to receive either 10 (range 8–12) or 20 (range 16–24) mg/kg/day rectal artesunate for 3 days followed by 25 mg/kg oral mefloquine. The study endpoints were fever clearance time, parasite clearance time and proportion of patients with recrudescence. Serum levels of artesunate and dihydro-artemisinin were measured after the first dose of rectal artesunate in 16 subjects. Results: Both regimens were safe and effective. The cure rate was 100% in the 53 patients who completed 28-day follow-up. All of the study endpoints were comparable between both treatment groups. Conclusion: A regimen of rectal artesunate 10 mg/kg/day for 3 days followed by mefloquine 25 mg/kg is optimal for the treatment of uncomplicated falciparum malaria. There was no definite benefit from increasing the dosage of rectal artesunate from 10 to 20 mg/kg/day