We previously reported that low doses of interleukin-1 strongly inhibited in vitro development of the hepatic stages of Plasmodiumfalciparum and P. yoelii. Among several hypotheses, we considered the role of C-reactive protein (CRP), a major acute-phase reactant whose concentration increases markedly in infectious disorders. We demonstrated that human hepatocytes cultured in the presence of interleukin-1 released, as early as 30 min after stimulation, an increased amount of CRP. We then established that CRP bound to the P. falciparum and P. yoelii sporozoite surface membranes, probably via a phosphorylcholine binding site. Experiments in which CRP was added to rat hepatocyte monolayers during or after inoculation confirmed that the target of the CRP-mediated inhibition was at the very early phase of infection. These in vitro functional activities were confirmed in an in vivo model; rats with increased levels of CRP in serum following an injection of turpentine oil were found to be largely protected against an inoculation of P. yoelii sporozoites. The same results were observed in animals inoculated with sporozoites previously incubated in purified CRP or in sera of rats pretreated with turpentine oil. The latter effect was inhibited after incubation of serum from turpentineinjected rats with anti-CRP serum.