A high incidence of autologous graft-versus-host-disease (auto-GVHD) was observed after an alemtuzumab-containing conditioning regimen and autologous stem cell transplantation (auto-SCT) for chronic lymphocytic leukemia (CLL). Skin rash developed in almost all surviving patients (87%). In 7 patients (58%), a diagnosis of auto-GVHD was made (compared with 0% after TBI/Cy; P = .01). All patients with auto-GVHD required immunosuppression, and 3 of 7 were hospitalized because of GVHD. The median duration of GVHD was 517 days (range, 60-867 days). Auto-GVHD was associated with an abnormally high CD4/CD8 ratio because of severe depletion of CD8(+) T cells, pointing to a potential pathomechanism. High non-relapse-related mortality led to the discontinuation of the trial. Current results do not support the use of high-dose alemtuzumab combined with total body irradiation (TBI) and autologous stem cell transplantation (auto-SCT). However, the addition of alemtuzumab led to improved disease control at the molecular level. Longer follow-up will show whether the GVHD-like syndrome may contribute to prolonged minimal residual disease (MRD) negativity.