The viral CC chemokines MC148, encoded by the poxvirus molluscum contagiosum, and viral macrophage inflammatory protein (vMIP)-I and vMIP-II, encoded by human herpesvirus 8, were probed on the murine CC receptor (CCR) 8 in parallel with human CCR8. In calcium mobilization assays, vMIP-I acted as a high-affinity agonist, whereas vMIP-II acted as a low-affinity antagonist on the murine CCR8 as well as the human CCR8. MC148 was found to bind and block responses through the human CCR8 with high affinity, but surprisingly MC148 was unable to bind and block responses through the murine CCR8. Because MC148 is the only high-affinity antagonist known to target and be selective for CCR8, MC148 is a valuable tool to decipher the role played by CCR8 in the immune system. This study shows that MC148 could not be used in murine inflammatory models; however, it will be interesting to see whether it can be used in other animal models to delineate the role played by CCR8.