Polymorphonuclear granulocytes, which provide a major defence against Streptococcus pneumoniae infections, are attracted to and activated by various cytokines. The aim of this study was to analyse the cytokine response of human peripheral blood mononuclear cells to stimulation with S. pneumoniae. Strains belonging to serogroups 4, 6, 14, 19 or 23, were isolated from nasopharynx, middle ear fluid, cerebrospinal fluid or blood. All strains induced a marked proliferative response of the peripheral blood mononuclear cells; the stimulatory index was 34 ± 11. High levels of pro-inflammatory cytokines were induced, i.e. interleukin (IL)-1β (53 ± 25 ng/ml), IL-6 (347 ± 41 ng/ml) and tumour necrosis factor (TNF)-α (15 ± 4 ng/ml). Also, chemokines and immunoregulatory cytokines including IL-8 (215 ± 224 ng/ml), IL-10 (122 ± 60 pg/ml), IL-12 (1195 ± 648 pg/ml), interferon (IFN)-γ (18 ± 4 ng/ml) and granulocyte macrophage colony-stimulating factor (135 ± 80 pg/ml) were induced. Several of these cytokines can up-regulate phagocytosis and the killing of bacteria. Interestingly, strains isolated from middle ear fluid and blood elicited significantly fewer IL-8 and significantly more IL-12 and IL-10 than strains from nasopharynx. They also induced a stronger proliferative response. Our results indicate that pneumococci are potent inducers of cytokines, especially IL-12, favouring T-helper cell type 1 (Th1) responses.