Depression is a typical psychiatric disorder with a lifetime prevalence rate of approximately 15%. Although the details of the pathogenesis of depression are still unknown, inflammation is considered as the underlying mechanism leading to depression. The chemokine receptor CCR4 is a major regulator of migration of regulatory T cells (Tregs) and Th17 cells. It has been reported that serum levels of CCR4 ligands are increased in patients with depression. However, the involvement of CCR4 in the pathogenesis of depression is still unknown. Here, we investigated the role of CCR4 in depression using a lipopolysaccharide (LPS)-induced depression mouse model. We found that CCR4-deficient mice displayed a significant increase in immobility time in the forced swim test. Flow cytometry analysis revealed that LPS-induced increase in Treg, but not Th17 cell, migration into the brain was decreased in CCR4-deficient mice. Moreover, CCR4 deficiency increased M1 macrophages were increased, while M2 macrophages were decreased in the brain. Similar to CCR4-deficient mice, treatment with selective CCR4 inhibitor decreased Tregs and M2 macrophages in the brain and increased immobility time in the forced swim test. These results suggest that CCR4 suppresses depressive-like behavior via Treg migration into the brain and M2 macrophage polarization.