Plasma and peripheral blood mononuclear cells (PBMC) were obtained from P. falciparum-infected individuals with and without the sickle cell trait at diagnosis and 7 days after treatment. HbAA and HbAS patients were compared for levels of plasma soluble IL-2 receptors (IL-2R) and the in vitro cellular reactivity to affinity-purified soluble P. falciparum antigens (SPAg), PPD and phytohaemagglutinin (PHA). At diagnosis, HbAS patients with clinical disease had lower plasma-soluble IL-2R levels and parasite counts than the corresponding HbAA patients, whereas HbAS and HbAA patients with asymptomatic infections had comparable soluble IL-2R levels and parasite counts. PBMC from HbAS patients had higher proliferation and IFN-gamma production in response to SPAg than PBMC from HbAA patients. The difference in the lymphoproliferative responses to SPAg between the two groups was evident in patients with asymptomatic infections. In all patients, the clinical severity, the soluble IL-2R levels and the parasite counts were directly related. The former two were inversely related to the proliferative responses to SPAg. After treatment, all the studied parameters were comparable in the two groups. The study indicates that during P. falciparum infection, HbAS compared with HbAA patients had lower in vivo cellular activation and higher in vitro cellular reactivity in response to soluble malaria antigens.