The β2 integrins play a key role in inflammation and immune responses. The β2 integrin CD11b has been shown recently to be important in the maintenance of tolerance; however, the underlying mechanisms remain to be fully understood. Natural killer (NK) cells are an important effector of innate immunity but are also a regulator of adaptive immune response. How the activating and inhibitory signals are balanced to determine NK cell function needs to be further identified. CD11b expression was dramatically up‐regulated on NK cells once they matured and became activated; therefore, we investigated the role of inducible CD11b in the regulation of NK cells. Neutralizing anti‐CD11b antibody enhanced cytotoxicity, interferon‐γ (IFN‐γ) and granzyme B production of Toll‐like receptor 3 (TLR3)‐triggered NK cells. CD11b‐deficient NK cells stimulated with or without the TLR3 ligand polyinosinic:polycytidylic acid [poly(I:C)] exhibited more potent cytotoxicity, and higher production of IFN‐γ and granzyme B. Through in vivo depletion of NK cells and adoptive transfer of CD11b‐deficient NK cells, we demonstrated that CD11b‐mediated suppression of NK cell function was responsible for attenuation of poly(I:C)‐induced acute hepatitis by CD11b. Conclusion: Our findings demonstrate that CD11b negatively regulates NK cell activation and thus attenuates poly(I:C)‐induced acute hepatitis. Our study provides a new mechanistic explanation for maintenance of tolerance and control of inflammation by CD11b. (HEPATOLOGY 2009.)