Forty-two healthy Caucasian subjects were randomized in a double-blind, parallel three-group study (14 subjects per group) to investigate potential electrocardiographic and pharmacokinetic interactions between the antimalarials artemether-lumefantrine (six-dose regimen of Riamet over 3 days) and quinine (2-h intravenous infusion of 10 mg/kg body weight, not exceeding 600 mg in total, 2 h after the last dose of Riamet). The study medications were all safe and well tolerated after all treatments. Neither the pharmacokinetics of lumefantrine nor the pharmacokinetics of quinine was influenced by the presence of the other drug. Plasma levels of artemether and dihydroartemisinin appeared to be lower following the combined treatment Riamet + quinine, but this was not considered to be clinically relevant. Riamet alone had no effect on QTc interval. Infusion of quinine alone caused a transient prolongation of QTc interval, which was consistent with the known cardiotoxicity of quinine, with this effect being slightly but significantly greater when quinine was infused after Riamet. It would thus appear that the inherent risk of QTc prolongation of IV quinine was enhanced by prior administration of Riamet. However, these occasional QTc prolongations, which were small in magnitude and not correlated with plasma concentrations of any of the compounds, were not considered to be of clinical importance. In conclusion, overlapping therapy with artemether-lumefantrine and IV quinine in the treatment of patients with complicated or multidrug-resistant Plasmodium falciparum malaria may result in a modest increased risk of QTc prolongation, but this is far outweighed by the potential therapeutic benefit.