Artemisinin-based combination therapies (ACT) are now being adopted as first-line treatments against uncomplicated malaria in sub-Saharan Africa. Between December 2009 and February 2010, the efficacies of two ACT - dihydroartemisinin-piperaquine (DHA-P) and artemether-lumefantrine (AL) - in the treatment of uncomplicated Plasmodium falciparum malaria were compared in Sinnar, central Sudan. Overall, 149 patients (75 given DHA-P and 74 given AL) completed the 28 days of follow-up. All the patients were found to be afebrile and aparasitaemic on day 3. By day 28, only one patient, who had been given AL, showed late treatment and parasitological failures, while each of the other 148 patients showed an adequate treatment response. After the results of a PCR-based assay confirmed that the recrudescent parasitaemia was probably the result of treatment failure, the frequencies of cure by day 28 were calculated as 100% for DHA-P and 98.7% for AL (P>0.05). None of the patients was found gametocytaemic during the follow-up, and the adverse effects observed were mild (nausea, vomiting, abdominal pain, dizziness and/or rash), resolved spontaneously and occurred in only five patients in each treatment arm. Thus, both treatments appeared effective and safe for the treatment of uncomplicated P. falciparum malaria in central Sudan, although treatment with DHA-P (which requires a simpler dosing regimen) might be preferred to treatment with AL.