Given the profound sensitivity of patients with Fanconi anemia to conventional conditioning regimens before hematopoietic stem cell transplantation (HSCT), we developed a minimally toxic regimen consisting of 2 Gy total body irradiation, 90 mg/m2 fludarabine, and postgrafting immunosuppression with cyclosporine and mycophenolate to treat FA patients undergoing HSCT from HLA-matched unrelated donors. With over 10 months follow-up, our first patient has complete and sustained engraftment. Graft-versus-host disease was limited to mild skin and liver and moderate gut manifestations. We conclude that the approach is well tolerated and ideally suited to reduce regimen-related toxicities while achieving sustained engraftment.