Interleukin-12 (IL-12) is a proinflammatory cytokine secreted by antigen-presenting cells (APC) in response to microbial antigens and mitogens. IL-12 induces interferon-gamma (IFN-gamma) production and enhances cellular immune responses. Conversely, IFN-gamma does not induce IL-12 but can prime its production by phagocytic cells in response to antigenic stimuli. In this study, we examined the effect of IFN-beta on IL-12 production in human macrophages, as IFN-beta is a natural protein produced by virus-infected cells. We demonstrate that, unlike IFN-gamma, IFN-beta is able to induce IL-12 production in macrophages. However, IFN-gamma can enhance IFN-beta-induced IL-12 in these cells. These findings suggest that IFN-beta could influence the immune response to virus infection indirectly through IL-12.