Heat-stable antigens of rodent malarial parasites induce the release of tumour necrosis factor (TNF) from mouse macrophages, in vitro and in vivo. We report here that analogous antigens of Plasmodium falciparum trigger the release of TNF from human monocytes in vitro, in conditions that exclude the effects of any contaminating endotoxin. These antigens also induced TNF release from a murine monocytic cell line and from the peritoneal macrophages of several strains of mice, including the LPS-hyporesponsive C3H/HeJ mice. Similarly, boiled soluble antigens from the rodent parasites P. yoelii and P. berghei also stimulated human monocytes. Antisera made by immunizing mice with boiled antigens of P. falciparum or P. yoelii inhibited the stimulation of TNF secretion by P. falciparum antigens. They did not block the induction of TNF by bacterial lipopolysaccharide. Thus mouse macrophages provide a convenient system for investigating the nature, cross-reactions and antigenic variation of human malarial soluble antigens. Since these are known to occur in the circulation of patients with malaria, they may be responsible for excess production of TNF, a mediator that is thought to play a central role in the pathogenesis of the disease.