Glucose metabolism, the prime energy-generating system of intraerythrocytic Plasmodium berghei in rats, is markedly inhibited in vitro by 4,4′-diaminodiphenylsulfone (DDS) at drug concentrations that can be attained in vivo at oral doses of between 100 and 250 mg per kg. This inhibition appears to originate through interference with glucose transport at the level of the host's red-cell membrane, in contrast to a direct effect upon the intracellular parasite, since the inhibition is antagonized by raising medium glucose concentrations. DDS does not inhibit the glucose metabolism of the erythrocyte-freed parasite, and DDS also inhibits the uptake of glucose by unparasitized rat blood cells. A demonstrated ability of red cells, both parasitized and unparasitized, to concentrate DDS at the red-cell surface could help to explain the inhibition. Para-aminobenzoic acid (PABA), when incubated with DDS at equimolar concentrations, had no apparent effect upon the DDS inhibition of intraerythrocytic parasite glycolysis. The results of these investigations suggest that DDS may exert antimalarial actions by means other than the inhibition of parasite folic-acid synthesis through interfering with PABA utilization. First, the inhibition of glucose utilization by the parasite in itself might constitute an important antimalarial effect. Second, this DDS inhibition of parasite glucose metabolism may still involve interference with parasite folic-acid synthesis since the synthesis de novo of folates by bacteria and presumably by the malaria parasite seems dependent upon an active glycolytic glucose metabolism.