A novel difluorinated 3,3'-spirocyclopentane 1,2,4-trioxane ('Fenozan-50F') is a potent blood schizontocide against drug-sensitive and drug-resistant rodent malaria parasites. It also exerts some action against pre-erythrocytic schizogony, is a potent gametocytocide, and exerts a direct sporontocidal effect in infected mosquitoes. In the '4-day test' the ED90s are 6.8 and 6.0 mg/kg/day for four consecutive days by the subcutaneous and oral routes respectively against drug-sensitive Plasmodium berghei N, and 6.3 and 25 mg/kg against chloroquine-resistant P. yoelii NS in vivo. By the oral route against P. berghei N infection in mice, Fenozan-50F is about half as active as arteether but nearly three times as active as sodium artesunate. The activity of Fenozan-50F is retained against a wide spectrum of drug-resistant parasite lines, although those highly resistant to quinine or to artemisinin are less responsive at the ED90 level. At the ultrastructural level the compound, when administered to infected mice, causes marked changes in the membranes and ribosomes of trophozoites and young schizonts and of immature gametocytes, although few changes are apparent in mature gametocytes. Its toxicity appears to be very low when it is administered to mice by either the oral or subcutaneous route. Fenozan-50F is considered to be a good candidate for eventual use as a therapeutic agent for infection with polyresistant malaria in man.