The role of Plasmodium falciparum and blood monocytes in the erythrocyte damage and pathogenesis of anemia has been investigated using two strains of the parasite; one laboratory-established strain (FSJ-M) and one wild, fresh, clinical isolate (PfPGI). Peripheral blood monocyte-induced growth inhibition of the parasites, erythrocyte membrane lipid peroxidation as seen by the formation of lipid peroxide products, and sensitivity to peroxide hemolysis at atmospheric oxygen were evaluated. The growth inhibition of FSJ-M by activated blood monocytes was greater than that of PfPGI. The extent of lipid peroxidation and sensitivity to hemolysis increased significantly as the parasites matured. These adverse effects were more marked following exposure to activated monocytes, especially in synchronized, parasitized RBCs. In addition, uninfected erythrocytes within the PfPGI parasite culture revealed a significant increase in the lipid peroxide formation (P < 0.01) and susceptibility to lysis (P < 0.05) under similar oxidant stress induced by monocytes from normal healthy donors. Furthermore, there was a direct correlation between membrane lipid peroxidation and peroxide hemolysis, both before and after monocyte exposure, suggesting a primary role of membrane peroxidation in red cell lysis. The contribution of intraerythrocytic parasites and nonspecific activation of blood monocytes in the pathophysiology of erythrocyte damage and anemia of P. falciparum infection is discussed.