The polyunsaturated fatty acids docosahexaenoic acid (C22:6,n-3), eicosapentaenoic acid, arachidonic acid, and linoleic acid caused marked in vitro growth inhibition of Plasmodium falciparum, assessed by a radiometric assay. In contrast, negligible parasite killing was seen with oleic acid or docosanoic acid. Parasite killing was significantly increased when oxidized forms of polyunsaturated fatty acids were used. Antioxidants greatly reduced the fatty acid-induced killing. Mice infected with P. berghei and treated for 4 d with C22:6,n-3 showed marked reduction in parasitemia. The anemia associated with the infection was also alleviated by treatment with C22:6,n-3. The data provide new information that could be explored in order to develop new strategies in malaria treatment.