Interleukin-10 plays important yet contrasting roles in both the septic response and in the evolution of bacterial pneumonia. To determine the role of IL-10 in host defense against Acinetobacter baumannii infection, wild-type (WT) and IL-10-deficient mice were infected intranasally with the bacteria. Survival rate, the change of body weight, the level of cytokines and chemokines in lung lysate, and lung histopathology were examined. 73% of IL-10 deficient mice (13/21) were died during experimental period, whereas all WT mice survived. The pulmonary bacterial loads were significantly higher in IL-10-deficient mice, as compared with WT mice at 3 day after infection, although there was no significant difference at 1 day after infection. The level of IL-6, TNF-α, CXCL, CCL2, IFN-γ, and IL-1β was higher in lung lysate of IL-10 deficient mice as compared with that of WT mice. Moreover, histological findings showed that lung inflammation was much severe in IL-10 deficient mice. Endogenous IL-10 was essential for optimal phagocytic activity of macrophages, and treatment of recombinant IL-10 enhanced the ability of phagocytosis and bacterial killing in macrophages. Also, intranasal administration of recombinant IL-10 rescued mice from lethality by lung infection of A. baumannii. Our results show that IL-10 plays an important role in the host defense against pulmonary infection of A. baumannii.