IL-10 is a potent, endogenous anti-inflammatory cytokine known to decrease cytokine and chemokine expression. Traditionally, in vivo effects of IL-10 were extrapolated from studies employing systemic antibody neutralization. As a result, divergent data regarding the protective and/or harmful roles of IL-10 have been reported. In this study, we used a lung-specific, tetracycline-inducible IL-10 over-expression transgenic (IL-10 OE) mouse to study the effects of IL-10 over-expression on Pseudomonas aeruginosa-induced lung inflammation and corresponding survival in mice. Over-expression of IL-10 in the lung significantly increased mortality. During the early phase following infection (6 hours post-infection), neutrophil recruitment as well as cytokine (TNF-) and chemokine (KC) expression were significantly decreased in the IL-10 OE mice which resulted in attenuated bacterial clearance. At the later stage of infection (24 hours post-infection), overzealous production of KC and TNF-, intensified neutrophil infliltration and increased vascular leakage were observed in IL-10 OE mice. Neutrophil depletion showed impaired bacteria clearance in both control and IL-10 OE mice and further enhanced mice mortality. Our data indicated that early neutrophil recruitment is important for combating bacterial infection and the inhibition of neutrophil recruitment by IL-10 resulted in insufficient bacteria clearance in the lung which lead to excessive development of inflammation and increased mice mortality.