The present report summarizes our experience in applying a new approach in bone marrow transplantation for the treatment of beta-thalassemia major. Ex-vivo pretransplant T-lymphocyte depletion with CAMPATH-1 was used for prevention of acute and chronic graft versus host disease and total lymphoid irradiation was added for the conditioning regimen for abrogation of potential rejection of T-cell depleted marrow allografts. Ten patients with homozygous beta-thalassemia major were 9-48 months of age (median 18.5 months) and received HLA-identical allogeneic T-cell depleted marrow after treatment with total lymphoid irradiation, busulfan and cyclophosphamide. Seven patients are alive and free of disease, 3-46 months post-transplantation. The actuarial probability of survival and of disease-free survival at two years was 70%. Three patients died: one of intracranial hemorrhage post-transplantation, one from busulfan interstitial pneumonitis, and one who rejected the first graft and developed fatal chronic graft versus host disease after a second transplant. Seven patients are alive and well with follow-up of 3-45 months, with no signs of acute or chronic GVHD. We conclude that T-cell depleted bone marrow transplantation is indicated for homozygous transfusion dependent young patients with beta-thalassemia who are minimally transfused, particularly in areas where optimal conventional therapy is not feasible.