In the present study, we explored the molecular mechanisms by which bacterial endotoxin (LPS) mediates the down‐regulation of CCR2 receptors on human monocytes. We found that LPS induced a marked reduction in CCR2 cell surface protein levels which was blocked by pretreatment with the tyrosine kinase inhibitors genistein and herbimycin A. The effector mechanism underlying LPS‐induced CCR2 down‐modulation appears to involve the enzymatic activity of proteinases since Western blot analysis of LPS‐stimulated monocytes revealed the degradation of a 38‐kDa species corresponding to the CCR2B monomer. In RBL cells expressing the CCR2B‐green fluorescent protein (GFP) fusion chemokine receptor, LPS stimulated the internalization and degradation of CCR2. The serine proteinase inhibitor N‐α‐p‐tosyl‐L‐lysine chloromethyl ketone blocked LPS‐induced down‐modulation of CCR2 in monocytes and CCR2B‐GFP in RBL cells. This work describes a previously uncharacterized mechanism for CC chemokine receptor down‐modulation that is dependent upon tyrosine kinase activation and serine proteinase‐mediated receptor degradation and may provide further insight into the mechanisms of leukocyte regulation during immunological and inflammatory responses.