Because interleukin-18 (IL-18) is similar to IL-1 and is known to be involved in the hematopoietic progenitor cell growth, the effect of IL-18 on circulating cell populations was examined. Repeated administration of IL-18 induced significant amounts of neutrophilia in mice. In parallel, high levels of interferon-γ (IFN-γ), IL-6, and granulocyte-macrophage colony-stimulating factor (GM-CSF) were detected in the serum of these mice. Interestingly, the cytokine profiles as well as the cell populations in circulation altered around 2 weeks after the beginning of IL-18 administration. A weak but definite eosinophilia was observed concurrently with the appearance of serum IL-5. Consistent with these observations, IL-18 induced secretion of IFN-γ, GM-CSF, and IL-6 from splenocytes in culture. IL-18 also induced low levels of IL-5 in the splenocyte culture, which was inhibited by IL-12. However, markedly high levels of IL-5 were secreted into the culture medium when splenocytes from IFN-γ–deficient mice were stimulated by IL-18. CD4+ T cells strongly responded to IL-18 to secrete IL-5 and GM-CSF. IL-18 stimulated secretion of IL-6 and expression of G-CSF mRNA in splenic adherent cells. Expression of IL-18 receptors was detected in CD4+ T cells and splenic adherent cells (macrophages). These results show that IL-18 stimulates CD4+ T cells and macrophages to secrete IL-5, GM-CSF, IL-6, and granulocyte–colony stimulating factor in the absence of IL-12, which in turn induces hematopoietic cell proliferation causing neutrophilia and eosinophilia in mice.