The CC chemokine ligand 2 (CCL2) and CC chemokine receptor 2 (CCR2) are expressed in the heart after infection with Trypanosoma cruzi, suggesting that they play an important role in host defense. Infection of CCR2-deficient (CCR2(-/-)) mice with T. cruzi resulted in increased cardiac parasitism, yet the severity of cardiac inflammation was not affected. In addition, expression of interferon- gamma and inducible NO synthase in the heart, which are associated with effective killing of trypomastigotes, was not affected in CCR2(-/-) mice. These observations reveal that CCR2 signaling plays a distinct role that is separate from that of influencing either chemotaxis or previously defined anti-trypomastigote mechanisms for the control of T. cruzi's replication in the heart.