The plasma membrane glycoprotein re- ceptor CD163 is a member of the scaven- ger receptor cystein-rich (SRCR) super- family class B that is highly expressed on resident tissue macrophages in vivo. Pre- viously, the molecule has been shown to act as a receptor for hemoglobin- haptoglobin complexes and to mediate cell-cell interactions between macro- phages and developing erythroblasts in erythroblastic islands. Here, we provide evidence for a potential role for CD163 in host defense. In particular, we demon- strate that CD163 can function as a macro- phage receptor for bacteria. CD163 was shown to bind both Gram-positive and -negative bacteria, and a previously iden- tified cell-binding motif in the second scavenger domain of CD163 was suffi- cient to mediate this binding. Expression of CD163 in monocytic cells promoted bacteria-induced proinflammatory cyto- kine production. Finally, newly generated antagonistic antibodies against CD163 were able to potently inhibit cytokine pro- duction elicited by bacteria in freshly isolated human monocytes. These find- ings identify CD163 as a macrophage receptor for bacteria and suggest that, during bacterial infection, CD163 on resi- dent tissue macrophages acts as an in- nate immune sensor and inducer of local inflammation. © 2009 by The American Society of Hematology.