Interleukin-18 (IL-18) is a novel proinflammatory cytokine with potent interferon (IFN)-lambda inducing activity that plays an important biological role in the enhancement of the activity of natural killer cells and cytotoxic T lymphocytes. In this study, we have identified a novel short form of IL-18 in mouse, named IL-18s. IL-18s might be an alternative splicing variant of IL-18 and its cDNA contains a 57 bp in-frame deletion. Like IL-18, IL-18s is also widely expressed in mouse tissues. It was suggested that IL-18s might have a caspase-1-dependent mechanism for maturation and secretion similar to that of IL-18: when transfected in COS-7 cells, pro-IL-18s (22 kDa) could be detected, and the mature IL-18s (16 kDa) could also be detected when combined with caspase-1. We observed that recombinant mouse IL-18s did not show any IL-18-like function, and IL-18s could enhance the ability of IL-18 to increase IFN-lambda production by approximately 40% in mouse splenocytes. This effect was observed primarily at relative low concentrations of IL-18, suggesting that IL-18s might regulate the activity of IL-18 in the physiological conditions.