BACKGROUND Children with chemotherapy refractory T-cell lymphoblastic leukemia/lymphoma were given alpha-interferon (alpha-IFN) to evaluate the efficacy and toxicity of this biologic response modifier. METHODS Twenty children with T-cell acute lymphoblastic leukemia (T-cell ALL) in marrow relapse and one patient with mediastinal recurrence of T-cell non-Hodgkin's lymphoma (T-cell NHL) were enrolled. All patients had failed at least two previous multiagent drug trials. Recombinant alpha-IFN was given at 30 million U/M2/dose intravenously or subcutaneously for 10 doses over 14 days, followed by 3 doses per week until disease progression occurred. RESULTS One child had a complete response (< 5% blasts) and three patients a partial response (5-25% blasts) in their bone marrow. All patients eventually showed signs of progressive disease. Significant toxicities included cardiac hypofunction in two patients and profound lethargy in two patients. CONCLUSIONS alpha-IFN is tolerated in children with T-cell ALL and T-cell NHL and has activity against chemotherapy resistant disease.