Background Osteopontin (OPN) is a multifunctional glycoprotein with pro-inflammatory properties. In severe sepsis, levels of plasma OPN are significantly higher in non-survivors than in survivors. We hypothesized that OPN results in greater inflammation and worse outcome through modulation of endogenous glucocorticoid production in sepsis. Methods and Results Sepsis was induced by cecal ligation and puncture (CLP) in wild type (WT) and OPN gene knockout (OPN-/-) mice. In response to sepsis, the OPN-/- mice had lower levels of plasma cytokines and chemokines than the WT mice. The levels of corticosterone in plasma were similar between WT and OPN-/- sham animals but they increased 24 h after CLP induction in the WT mice, but not in the OPN-/- mice. The mortality rate was lower in the OPN-/- mice than in the WT mice. Conclusion OPN is associated with greater inflammatory response and increased mortality, despite the higher corticosterone levels in plasma. Corticosterone production is not impaired in the absence of OPN.