The mortality of sepsis is increasing and conventional therapies for it have no better therapeutic effects. We investigated the effects of adiponectin (APN) on mortality and high mobility group box 1 (HMGB1) in polymicrobial sepsis mouse models. Sepsis models were established by cecal ligation and puncture (CLP) in BALB/c mice. Animals were randomly divided into four groups including control group (C group), model group (CLP group), early APN treatment group (APN + CLP group), and late APN treatment group (CLP + APN group). Mice in each group were killed at 6, 12, 24, and 48 hr after CLP, respectively, to collect samples for determining the levels of serum interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), high mobility group protein-1 (HMGB1), and the expression of lung tissue HMGB1 mRNA. The survival curves in the four groups were drawn. The mortality rates were significantly lower in APN + CLP (30%) and CLP + APN (40%) groups than in CLP group (80%) seven days after CLP. Serum levels of cytokines (IL-6 and TNF-α) and HMGB1 were significantly reduced (p < .05) in APN + CLP and CLP + APN groups compared with those of CLP group. There was a significant correlation between serum HMGB1 and lung HMGB1 mRNA (r = 0.891). The levels of HMGB1 and HMGB1 mRNA were higher in CLP, APN + CLP, and CLP + APN groups than in C group (p < .01), but were lower in APN + CLP and CLP + APN groups than in CLP group (p < .01). APN can reduce the mortality rate and plays an anti-inflammatory role in polymicrobial sepsis mouse models through inhibiting HMGB1.