Donor alloreactive CD4⁺ T cells are important to the pathogenesis of chronic graft-versus-host disease (cGVHD), but specific subsets of CD4⁺ T cells responsible for GVHD have not been defined. We hypothesized that cGVHD might be associated with a preponderance of CD4⁺ effector memory cells (CCR7^–/CD62L^low, CD4_EM). We analyzed CCR7 and CD62L expression on CD4⁺ T cells from stem cell transplantation patients, who did or did not develop cGVHD, and healthy donors. Patients with cGVHD had a higher percentage of CD4_EM cells (35.5% ± 2.9%) than healthy donors (13.8% ± 0.7%; P < .0001) or patients without cGVHD that received a transplant (21.7% ± 2.1%; P < .01). Using corticosteroid dose as a surrogate marker for cGVHD severity, severe cGVHD was associated with a higher percentage of CD4_EM cells. The proportion of CD4_EM cells in corticosteroid-dependent patients with systemic lupus erythematosis or Wegener granulomatosis did not differ from patients without cGVHD that received a transplant. This finding implies that overrepresentation of CD4_EM cells is a unique feature of cGVHD.