IL-18 has a potential to up-regulate the Th1 and Th2 immune responses. It is known that IL-18, in synergy with IL-12, augments the Th1 response to bacterial infections, but it also augments the Th2 response to allergic disorders in the absence of IL-12. Although the Th1 and Th2 immune responses cross-regulate each other, our recent murine studies have demonstrated that multiple, alternate-day IL-18 injections (but not a single injection) could augment not only the Th1 immune response but also the Th2 immune response, including IgM production against bacterial infection in mice. In addition, critically ill patients who suffer from severe surgical stresses, e.g., trauma injury, burn injury, and major surgery, are known to be highly susceptible to bacterial infections/sepsis, and their outcomes become extremely poor as a result of infectious complications. Their host defense systems against infections, such as Th1-mediated cellular immunity, Th2-mediated humoral immunity, and neutrophil-mediated immunity, are impaired severely and multifactorially. Although simultaneous enhancement of these immune responses may be ideal for such immunocompromised patients, its achievement appears to be difficult because of the cross-regulating effect of the Th1 and Th2 responses. However, multiple IL-18 injections into mice can effectively restore these impaired immune responses in the immunocompromised mice receiving severe burn injury or splenectomy, thus improving their survival after bacterial infections. Therefore, IL-18 treatment may be an attractive and useful therapeutic tool against bacterial complications in immunocompromised hosts after severe surgical stress.