Carbon monoxide (CO), a catabolic product of heme degradation, is an efficacious cytoprotectant and potent anti-inflammatory molecule. One of the important cellular targets of carbon monoxide is the macrophage, a key modulator of inflammation. In this study we investigated the effects of CO on the ability of cultured macrophages to phagocytose E. coli. Exposure to CO augmented E. coli phagocytosis but had no effect on inert particulate matter internalization. The ability of CO to increase uptake of the bacteria was in part mediated by the redistribution and increased expression of Toll-like receptor 4 (TLR4) on the cell surface. Furthermore, inhibition of p38 MAPK attenuated CO/E. coli-induced surface expression of TLR4 and abrogated the CO effects on E. coli phagocytosis. Collectively these data show that CO enhances the rate of E. coli phagocytosis via p38-mediated surface expression of TLR4 and suggest that CO may be a potential therapeutic modality by which to increase bacterial clearance.