The interactions of artemisinin with atovaquone, quinine, and mefloquine were investigated in three Plasmodium falciparum strains (strains F-32, FCR-3, and K-1) by an in vitro culture assay. The parasites were cultured for 48 h in the presence of different concentrations and proportions of two drugs at a time in a checkerboard design. The response parameters were determined, and the sums of the fractional inhibitory concentrations (⌺FICs) of the drug combinations were calculated for different degrees of inhibition (50% effective concentration [EC 50 The evolution and spread of multidrug-resistant Plasmodium falciparum malaria have prompted the need to use combinations of antimalarial drugs, preferably drugs with different modes of action, in order to increase drug efficacy and to potentially reduce the possibility of the development of resistance to either compound. Artemisinin and its derivatives are highly effective compounds against multidrug-resistant P. falciparum, with consistently rapid clearance of parasites and fever in patients with malaria (14). However, in monotherapy with artemisinin and its derivatives, a relatively long treatment course of 5 to 7 days is required; such a treatment course entails the risk of poor compliance and high recrudescence rates (8). Artemisinin therefore needs to be combined with a partner drug with a longer elimination half-life (t 1/2 ) in order to reduce the risk of recrudescence.In areas with multidrug resistance, i.e., mainly parts of Southeast Asia, the efficacy of mefloquine (as monotherapy) is compromised. Nevertheless, mefloquine and artesunate were found to be synergistic both in vivo and in vitro, and this combination is now widely recommended for clinical use in Southeast Asia (13,20,29). However, there is a need for drugs that can be alternative partners to artemisinin, especially in areas where malaria transmission is intensive and where the persistence of subinhibitory concentrations of mefloquine (elimination t 1/2 , 3 weeks) for long periods entails a high risk of selection of resistant parasite populations (25).Quinine, a quinoline methanol like mefloquine, represents one potential partner drug to artemisinin. There is relatively little resistance to the drug worldwide, and it has a t 1/2 of 9 to 18 h. There is yet little in vitro information and practically no in vivo data on the interactive profile of artemisinin and quinine.Atovaquone, a hydroxynaphthoquinone with a t 1/2 of 52 to 80 h, is a newly introduced antimalarial drug with a novel mode of action. It is well tolerated and active against both chloroquine-sensitive and -resistant strains of P. falciparum, but it should not be used alone for treatment or prophylaxis of malaria. It is formulated as a fixed combination with proguanil since the two drugs have shown a high degree of synergism both in vivo and in vitro (4,16,27). One in vitro study has been performed with the combination of artemisinin and atovaquone, but the results were inconclusive (4).The present study was conducted to assess poten...