Chronic graft-versus-host disease (GVHD) requires long-term immunosuppressive therapy after hematopoietic cell transplantation. We retrospectively analyzed a cohort of 751 patients with chronic GVHD to identify characteristics associated with the duration of immunosuppressive treatment. Among the 274 patients who discontinued immunosuppressive therapy after resolution of chronic GVHD before recurrent malignancy or death, the median duration of treatment was 23 months. Results of a multivariable model showed that treatment was prolonged in patients who received peripheral blood cells, in male patients with female donors, in those with graft-versus-host HLA mismatching, and in those with hyperbilirubinemia or multiple sites affected by chronic GHVD at the onset of the disease. Nonrelapse mortality was increased among patients with HLA mismatching or hyperbilirubinemia but not among those with other risk factors associated with prolonged treatment for chronic GVHD. Nonrelapse mortality was also increased in older patients and those with older donors, in patients with platelet counts less than 100 000/microL or progressive onset of chronic GVHD from acute GVHD, and in those receiving higher doses of prednisone immediately before the diagnosis of chronic GVHD. After the dose of prednisone was taken into account, progressive onset was not associated with an increased risk of nonrelapse mortality.