OBJECTIVES: The in vitro and in vivo efficacy and drug-drug interactions of the novel semi-synthetic endoperoxide artemisone with standard antimalarials were investigated in order to provide the basis for the selection of the best partner drug. METHODS: Antimalarial activity and drug interactions were evaluated in vitro against Plasmodium falciparum by the incorporation of [(3)H]hypoxanthine. In vivo efficacy and drug interactions were assessed using the standard 4-day Peters' test. RESULTS: Artemisone was 10 times more potent than artesunate in vitro against a panel of 12 P. falciparum strains, independent of their susceptibility profile to antimalarial drugs, and consistently 4 to 10 times more potent than artesunate in rodent models against drug-susceptible and primaquine- or sulfadoxine/pyrimethamine-resistant Plasmodium berghei lines and chloroquine- or artemisinin-resistant lines of Plasmodium yoelii. Slight antagonistic trends were found between artemisone and chloroquine, amodiaquine, tafenoquine, atovaquone or pyrimethamine and additive to slight synergistic trends with artemisone and mefloquine, lumefantrine or quinine. Various degrees of synergy were observed in vivo between artemisone and mefloquine, chloroquine or clindamycin. CONCLUSIONS: These results confirm the increased efficacy of artemisone over artesunate against multidrug-resistant P. falciparum and provide the basis for the selection of potential partner drugs for future deployment in areas of multidrug-resistant malaria. Artemisone represents an important addition to the repertoire of artemisinin combination therapies currently in use, as it has enhanced antimalarial activity, improved bioavailability and stability over current endoperoxides.