Abstract Background: Interferons (IFNs) are known to act synergistically with antineoplastic agents when applied to SCLC cell cultures. This study was conducted in order to detect the clinical benefits, if any, of the addition of IFN-alpha in the induction chemotherapy (CT) of SCLC patients. Patients and method: Ninety previously untreated patients with SCLC were randomly assigned to receive either CT alone (arm A) or CT plus IFNα-2a in a dose of 3 MU/m 2 twice weekly (arm B). CT for both arms consisted of carboplatin 420 mg/m 2, etoposide 200 mg/m 2 and ifosfamide 3.5 g/m 2 or epirubicin 80 mg/m 2 every 28 days for a total of eight cycles. Responding patients received primary site and prophylactic cranial irradiation and then had maintenance CT with cyclophosphamide 100 mg/m 2/day for 20 days every month. Patients in arm B received IFN throughout these treatments. Results: Eighty-one patients were evaluable for response, 39 in arm A and 42 in arm B. Both arms were comparable in terms of age, performance status and extent of disease. Overall response rates were not significantly different between the two arms (90% vs. 86%), although complete response rate was higher in arm B (38% vs. 28%). More importantly, Kaplan-Meier analysis disclosed a clear survival benefit in the arm receiving IFN-alpha ( P < 0.05). For limited disease the difference was even more significant ( P < 0.0067), while for extensive disease no significant difference was found ( P < 0.35). Fever, fatigue and anorexia were more frequent in arm B ( P < 0.001), as also leukopenia ( P < 0.01). Conclusion: The addition of IFN-alpha to induction CT appears to confer a survival benefit to SCLC patients but optimal dosing schedule has yet to be defined.