High mobility group box 1 (HMGB1) protein , a late mediator of lethality in sepsis, can induce acute inflammatory lung injury. Here, we identify the critical role of -chemokine receptors in the HMGB1 induced inflammatory injury and show that -chemokine receptor inhibition increases survival in sepsis, in a clinically relevant time frame. Intratracheal instillation of recombinant HMGB1 induces a neutrophilic leukocytosis, preceded by alveolar accumulation of the -chemokine MIP2, and accompanied by injury and increased inflammatory potential within the airspaces. To investigate the role of -chemokine receptors in the injury we instilled recombinant HMGB1 (0.5µg) directly into the lungs, and administered subcutaneous -chemokine receptor inhibitor, Antileukinate (200µg). -Chemokine receptor blockade, reduced HMGB1-induced inflammatory injury (neutrophils: 2.9 ± 3.2 vs 8.1 ± 2.4 x 10⁴cells; total protein:120 ± 48 vs 311 ± 129 µg/ml; reactive nitrogen species:2.3 ± 0.3 vs 3.5 ± 1.3 µM; and macrophage migration inhibitory factor:6.4 ± 4.2 vs 37.4 ± 15.9 ng/ml) within the bronchoalveolar lavage fluid, indicating that HMGB1 induced inflammation and injury are -chemokine mediated. Since HMGB1 can mediate late septic lethality, we administered Antileukinate to septic mice, and increased survival (from 58% in controls to 89%) even when the inhibitor treatment was initiated 24 hr after the induction of sepsis. These data demonstrate that -chemokine receptor inhibition can reduce HMGB1 induced lung injury and lethality in established sepsis, and may provide a novel treatment in this devastating disease.