Sickness behavior syndrome (SBS) as characterized by fatigue and depression impairs quality of life in patients with inflammatory diseases caused by infections and autoimmunity. Systemic engagement of CD40 in mice leads to an inflammatory syndrome with acute hepatitis, lymphadenopathy and development of SBS as evidenced by induction of sleep and weight loss. In the study presented here we show that the elimination of resident tissue macrophages in mice by antibody-mediated neutralization of colony-stimulating factor-1 receptor (CSF1R) did not prevent CD40 induced hepatitis, but conferred resistance to the development of SBS. The protective effect of CSF1R mAb on weight loss and behavior changes induced by CD40 activation coincided with the transformation of pro-inflammatory monocytes to IL-10 producing myeloid cells. In IL-10 knockout mice CSF1R neutralization failed to exert protection from the occurrence of SBS. This study establishes the unexpected key role of CSF1R in the polarization of inflammatory monocytes and thereby SBS in inflammatory liver diseases.