Abstract CCR2 and CCR5 are two chemokine receptors that are important in the pathogenesis of animal models of autoimmune diseases. Since the two receptors play complementary roles in the immune system, targeting both receptors simultaneously might afford greater efficacy than targeting either alone. The present study describes the identification and characterization of BMS-A, an orally bioavailable small-molecule CCR2/5-dual antagonist. BMS-A was identified as active against CCR2 and CCR5 in radioligand binding assays. Functional assays and biochemical studies demonstrate that it is a potent, selective, competitive, and reversible antagonist against both receptors. It is also a pan-antagonist in that it inhibits functional responses triggered by all ligands of both receptors. When studied in vivo in CCR2-dependent homeostatic and inflammatory models in mouse as well as monkey, BMS-A potently inhibits monocyte trafficking. Its in vivo activity against CCR5-mediated inflammatory processes was established in a CCR2-null mouse model of inflammation, wherein it further reduces macrophage infiltration into tissue. In mouse models of autoimmune disease, such as collagen-induced arthritis, BMS-A robustly reduces the clinical score and tissue destruction, as well as local and systemic inflammation. Thus, BMS-A is potentially a novel oral therapy for the treatment of autoimmune disease.