The anti-malarial action of quinoline-containing compounds depends on various membrane-related processes, and drug resistance could depend, among other factors, on the membrane lipid composition. To verify this hypothesis, the constitution of phospholipid classes and the content of cholesterol of various strains of Plasmodium falciparum-infected human erythrocytes grown in in vitro cultures have been assessed in conjunction with drug susceptibility. It was found that uninfected erythrocytes in the culture serve as a major source for the increased lipid content of malaria-infected cells. Alterations of the phospholipid composition of infected cells that result from parasite lipid metabolism are also reflected in the constitution of uninfected red cells, implying lipid exchange between infected and uninfected cells. An inverse relationship between the content of acidic phospholipids and cholesterol has been observed. Some strains resistant to chloroquine and quinine were sensitive to mefloquine, and vice versa. Resistance to chloroquine or quinine was found to be directly related to the content of acidic phospholipids, while that of mafloquine displayed an inverse correlation. Concomitantly, the resistance to chloroquine was inversely related to the content of cholesterol, while the sensitivity to mefloquine decreased with cholesterol concentration. The possible mechanisms that could account for these observations are briefly discussed.