In patients with malaria, the clinical manifestations of the disease are associated with the presence of high concentrations of tumour necrosis factor (TNF) in the serum. Blood-stage parasites of human and rodent malarial parasites release serologically related exoantigens which induce the production of TNF in vitro and in vivo and which can kill mice made hypersensitive to TNF by pretreatment with D-galactosamine. They also elicit the production of T-independent antibody, which blocks these effects. The capacity of the exoantigens to stimulate macrophages to secrete TNF does not require the presence of protein or carbohydrate, but is associated with a lipid whose activity can be abolished by treatment with phospholipase C. Treatments of the exoantigens which destroyed their activity in vitro also abrogated their immunogenicity and their toxicity for mice. No TNF-inducing activity could be detected in preparations of parasitized erythrocytes that was not associated with phospholipid, and the TNF-inducing properties of the malarial phospholipids are quite distinct from those of bacterial lipopolysaccharide. We conclude that release of potentially toxic phospholipids by parasites may be responsible for some of the pathology of malaria.