Chronic inflammation plays a critical role in promoting obesity-related disorders, such as fatty liver disease. The inflammatory cells that mediate these effects remain unknown. This study investigated the accumulation of immature myeloid cells in the liver and their role in liver inflammation. We found that the accumulation of immature myeloid cells, i.e., CD11b +Ly6ChiLy6G- cells, in the liver of B6 mice fed a high-fat diet contribute to liver inflammation. Adoptive transfer of CD11b+Ly6ChiLy6G- cells isolated from the liver of obese B6 mice, but not from lean B6 mice, resulted in liver damage that was evident by an increase in the activity of liver transferases in serum. CD11b+Ly6ChiLy6G- cells isolated from the liver of obese mice are more easily activated by way of Toll-like receptor (TLR) stimulation resulting in interleukin 12 and other inflammatory cytokine expression in an MyD88-dependent fashion. TLR7-activated CD11b +Ly6ChiLy6G- cells also enhance liver natural killer T cell (NKT) death in an Fas-dependent manner. Experiments using mice depleted of Gr-1+ immature myeloid cells demonstrated the important role of CD11b+Ly6ChiLy6G- in liver inflammation. Repeated injection of exosome-like particles causes CD11b + cell activation and subsequent homing to and accumulation of the cells in the liver. Conclusion: Consumption of a high-fat diet by B6 mice triggers an accumulation of immature myeloid cells in the liver. The immature myeloid cells release proinflammatory cytokines and induce NKT cell apoptosis. Activation-induced NKT apoptosis further promotes excessive production of Th-1 cytokines. This diet-induced accumulation of immature myeloid cells may contribute to obesity-related liver disease. Copyright © 2009 by the American Association for the Study of Liver Diseases.