One of recent developments in pain research is the finding that cytokines, including interleukin (IL) -1β, IL-6, TNFα, IL-17 and IL-10, have an important role in pain regulation. For example, IL-17 induces pain behavior, while IL-10 has an anti-nociceptive effect. IL-27 is a member of the IL-12 cytokine family and has been shown to have an immunosuppressive and anti-inflammatory role. The immunosuppressive effect of IL-27 is thought to depend on inhibition of the development of Th 17 cells (a newly identified inflammatory T-helper population) and on induction of IL-10 production. We tested pain behavior of mice which carry a null mutation in IL-27 or IL-27 receptor gene(s) because we expected that IL-27 may be able to suppress pain. IL-27 is a heterodimer of EBI3 and p28, while the IL-27 receptor consists of a specific receptor WSX-1, together with gp130, which can also be coupled with other cytokine receptors, such as the IL-6 receptor. We used 3 different mouse strains, each lacking one of these genes (apart from gp130). These mice appeared healthy and had no obvious abnormality by visual inspection. Interestingly, we found that they exhibited enhanced responses in various assessments of pain behavior, including the hotplate, von Frey and formalin tests. Furthermore intraperitoneal injection of recombinant IL-27 (rIL-27) normalized the pain threshold in EBI3 but not WSX-1 KO mice indicating that the normalized effect of rIL-27 was WSX-1-dependent, and that phenotypes observed in KO mice did not result from irreversible developmental changes. These results suggest that IL-27 might contribute to regulating normal sensation of pain even in healthy conditions without inflammation.