An open-label, pilot study was conducted to evaluate deferasirox/deferiprone combination chelation therapy in adult patients with transfusion-dependent thalassemia and severe iron overload. Enrollment proved difficult. Nine patients (median age, 27.4 y; ferritin, 4965 ng/mL; liver iron concentration, 28.5 mg/g dry weight; cardiac T2*, 13.3 ms) received treatment. Two were withdrawn for treatment-related adverse effects. Arthralgia (4 patients) and gastrointestinal symptoms (5 patients) were common; no episodes of neutropenia/agranulocytosis occurred. Adherence difficulties were common. Of 6 patients with 12 to 18 months follow-up, 3 showed improvement in cardiac T2* and 2 in liver iron. Combination oral chelation may be effective but adverse effects and adherence challenges may limit efficacy.