We studied the role of chemokine receptor CCR6 in acute graft-versus-host disease (GvHD), a pathology in which activated, host antigen-specific donor T cells selectively damage tissues such as skin, liver, and gut. GvHD incidence was reduced in major histocompatibility complex (MHC) class II–mismatched recipients of CD4⁺ T cells from CCR6-deficient donors. In MHC-matched/minor histocompatibility antigen–mismatched recipients of CD4⁺CD45RB^high T cells from CCR6-deficient donors, infiltration of CD45⁺ and CD4⁺ cells to skin and gut, as well as lesion onset, were significantly delayed, and pathologic symptoms were milder. Consistent with this, in skin and gut of recipients of naive T cells from CCR6-deficient donors we observed lower levels of interferon γ (IFN-γ), interleukin 10 (IL-10), and the chemokines that control activated T-cell homing. We suggest a role for CCR6 in recruiting alloreactive CD4⁺ T cells to target tissues and identify CCR6 as a potential therapeutic target for GvHD.