Advances in management of thalassemia have increased the proportion of patients living into adulthood. However, disease and treatment related complications in these patients progress over time causing severe morbidity and shortened life expectancy even in well-resourced countries with universal access to good medical treatment. Adult thalassemics constitute a high risk group of patients for transplantation due to both advanced age and acquired multiple organ damage. We present here long-term outcome after BMT for adult thalassemia and a new approach to transplant adult patients. Between November 1988 and September 1996, 107 consecutive patients (median age 22 years; range 17–35) received BMT from HLA-identical related donors following BU14/16 CY120/160 regimen. There were 18 class 2 and 89 class 3 patients. The probability of overall survival, event-free survival, mortality and rejection were 66%, 62%, 37% and 4% respectively. Interestingly, unlike class 3 younger patients (age <17 years) adult patients treated with the same treatment regimens had a low probability of rejection suggesting that donor-host tolerance might be induced even among extensively transfused patients. The incidence of grade 2–4 acute GVHD was 24.5%, and moderate or severe chronic GVHD was 5.6%. The presence of chronic active hepatitis at the time of transplant was the only factor associated with poor survival (RR 2.5; p=0.05). Sixty eight patients survive with a median follow-up of 12 years (range 8.3–16.2), and 66 of them are free of thalassemia. Current myeloablative BMT in adult patients is characterised by higher transplant related mortality due to the advanced stage of disease. Therefore, new approach to SCT that might reduce transplant related morbidity and mortality in adults is warranted. In 1997 we devised a new treatment protocol (Protocol 26) for adult thalassemics aimed at reducing the bone marrow and gradually increasing immunosuppression before transplant to avoid peritransplant drug toxicity. Patients were given hydroxiurea 30 mg/kg/day, azathioprine 3 mg/kg/day from day -45 through day -11, and fludarabine 20 mg/m2/day from day -17 through day -13 along with hypertransfusion and continuous chelation. On day -9 they started a reduced dose intensity conditioning regimen with BU14 CY90. Fifteen higher risk patients (median age 21 years; range 17–31) with class 3 thalassemia (n=14) or sickle cell anemia (n=1) were given BMT from HLA-identical siblings after preparation with this new protocol. Overall, treatment was well tolerated with no increase in toxicity. The probability of thalassemia-free survival and transplant related mortality were 67% and 27% respectively. Our new approach to transplant adult patients with a reduced dose intensity conditioning regimen showed some improvement in thalassemia-free survival but transplant related mortality in these high risk patients still remains elevated.