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High-mobility group box 1 (HMGB1) is a nucleoprotein with proinflammatory functions following cellular release during tissue damage. Moreover, antibody-mediated HMGB1 neutralization alleviates lipopolysaccharide (LPS)-induced shock, suggesting a role for HMGB1 as a superordinate therapeutic target for inflammatory and infectious diseases. Recent genetic studies have indicated cell-intrinsic functions of HMGB1 in phagocytes as critical elements of immune responses to infections, yet the role of extracellular HMGB1 signaling in this context remains elusive. We performed antibody-mediated and genetic HMGB1 deletion studies accompanied by in vitro experiments to discern context-dependent cellular sources and functions of extracellular HMGB1 during murine bloodstream infection with Listeria monocytogenes. Antibody-mediated neutralization of extracellular HMGB1 favors bacterial dissemination and hepatic inflammation in mice. Hepatocyte HMGB1, a key driver of postnecrotic inflammation in the liver, does not affect Listeria-induced inflammation or mortality. While we confirm that leukocyte HMGB1 deficiency effectuates disseminated listeriosis, we observed no evidence of dysfunctional autophagy, xenophagy, intracellular bacterial degradation, or inflammatory gene induction in primary HMGB1-deficient phagocytes or altered immune responses to LPS administration. Instead, we demonstrate that mice devoid of leukocyte HMGB1 exhibit impaired hepatic recruitment of inflammatory monocytes early during listeriosis, resulting in alterations of the transcriptional hepatic immune response and insufficient control of bacterial dissemination. Bone marrow chimera indicate that HMGB1 from both liver-resident and circulating immune cells contributes to effective pathogen control. Conclusion: Leukocyte-derived extracellular HMGB1 is a critical cofactor in the immunologic control of bloodstream listeriosis. HMGB1 neutralization strategies preclude an efficient host immune response against Listeria., (© 2021 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)