The signals that regulate the fate of circulating monocytes remain unknown. In the present study, we demonstrate that triggering of the NOD2 receptor by muramyl dipeptide (MDP) converts inflammatory Ly6C^high monocytes into patrolling Ly6C^low monocytes. Administration of MDP to Nr4a1^−/− mice, which lack Ly6C^low monocytes, or to Ly6C^low-depleted mice led to the emergence of blood-patrolling monocytes with a profile similar to that of Ly6C^low monocytes, including high expression of CX3CR1 and LFA1. Using intravital microscopy in animal models of inflammatory diseases, we also found that converted Ly6C^high monocytes patrol the endothelium of blood vessels and that their presence contributes to a reduction in the inflammatory response following MDP injection. Our results demonstrate that NOD2 contributes to the regulation of blood monocytes and suggest that it could be therapeutically targeted to treat inflammatory diseases.