Monocytes and macrophages play a significant role in host’s defense system, since they produce a number of cytokines in response to microbial infections. We have studied IL-1β, IL-18, IFN-α/β, and TNF-α gene expression and protein production in human primary monocytes and GM-CSF-differentiated macrophages during influenza A and Sendai virus infections. Virus-infected monocytes released only small amounts of IL-1β or IL-18 protein, whereas 7-and 14-day-old GM-CSF-differentiated macrophages readily produced these cytokines. Constitutive expression of proIL-18 was seen in monocytes and macrophages, and the expression of it was enhanced during monocyte/macrophage differentiation. Expression of IL-18 mRNA was clearly induced only by Sendai virus, whereas both influenza A and Sendai viruses induced IL-1β mRNA expression. Since caspase-1 is known to cleave proIL-1β and proIL-18 into their mature, active forms, we analyzed the effect of a specific caspase-1 inhibitor on virus-induced IL-1β and IL-18 production. The release of IL-1β and IL-18, but not that of IFN-α/β or TNF-α, was clearly blocked by the inhibitor. Our results suggest that the cellular differentiation is a crucial factor that affects the capacity of monocytes/macrophages to produce IL-1β and IL-18 in response to virus infections. Furthermore, the virus-induced activation of caspase-1 is required for the efficient production of biologically active IL-1β and IL-18.