The activity of 51 synthetic cis-fused cyclopenteno-1,2,4-trioxanes has been examined against drug-sensitive and chloroquine-resistant malaria parasites in vivo. Some of them display high levels of blood schizontocidal activity when administered orally or subcutaneously. They retain their activity against lines of parasites that are resistant to widely differing antimalarials such as 4-aminoquinolines, aminoalcohols, dihydrofolate reductase inhibitors and artemisinin. The most potent compound of the present series is cis-(+/-)-4a,7a-dihydro-6,7a-di(p-fluorophenyl)spiro [cyclopentane-3,3'-7H-cyclopenta-1,2,4-trioxin], otherwise known as Fenozan-50F.