Objective To investigate the effect of S100A9 protein on early immune function in mice with sepsis when injected intraperitoneally. Methods Experimental sepsis was induced by cecal ligation and puncture (CLP). 36 C57BL/6 mice were randomly divided into 3 groups (n=12 in each group): a sham group, a CLP group and a S100A9 group. One hour after operation, S100A9 protein was injected intraperitoneally to mice in the S100A9 group, while the same volume of normal saline was given to Sham and CLP group. 24 hours after surgery peripheral blood and peritoneal lavage fluid (PLF) were collected and the liver and lung of mice harvested from the living mice in each group. Bacterial loads were detected in blood and PLF. The levels of inflammatory factors TNF-α and IL-10 in blood were measured using ELISA. Counts of polymorphonuclear neutrophils (PMN), CD4+ and CD8+T cells in PLF were assayed using Flow Cytometry (FCM). The sections of liver and lung were stained by hematoxylin and eosin for histopathological examination. Results Bacterial loads in blood and PLF after CLP were (178.8±51.5)×103 and (246.6±49.8)×107 CFU respectively, they were significantly higher compared to Sham group (P<0.01). Bacterial loads in blood and PLF in the S100A9 group were (19.6±7.9)×103 and (47.8±18.6)×107 CFU respectively, and they were significantly lower compared to the CLP group (P<0.01). The level of anti-inflammatory cytokine IL-10 in CLP group was（296.2±7.4）pg/mL, and in S100A9 group it was （906.6±92.9）pg/mL (P<0.01), while the level of TNF-α was almost similar in these two groups. In CLP group only the number of PMN in PLF increased significantly when compared with sham group, it was （767.0±141.6）cells/μL (P<0.01). Number of PMN in PLF increased even more in S100A9 group, it was（1569.4±194.7）cells/μL (P<0.01). However, CD4+ and CD8+T cells in the S100A9 group also increased significantly when compared with CLP group, they were （702.0±167.4）cells/μL and （286.5±114.9）cells/μL (P<0.05 and <0.01) respectively. Histopathology also showed less injuries in liver and lung tissue in S100A9 group. Conclusions Injection of S100A9 could enhance the ability of clearing pathogens in peritoneal cavity, inhibit the over-aggressive inflammatory response, and attenuate liver and lung injury in mice with sepsis.