This study investigated the efficacy of long-term continuous and dose-escalated interferon-alpha (IFN) treatment in patients with progressive carcinoid tumors. In this single-institution, phase II study 16 chemotherapy-naive, eligible patients were entered. Interferon treatment consisted on 5 MIU IFN three times weekly s.c. until radiologic progression. In case of progression the dose was increased to 10 MIU. Radiologic and biochemical evaluation was done monthly and thereafter 3 monthly. We have treated 16 patients of whom 15 are evaluable for tumor response. Calculated by standard response criteria, three patients experienced a partial response. Another three had an important minor response. Median response duration was 24 months (range 18-51 months). Biochemical responses were observed in nine out of 12 patients with an elevated 5-hydroxyindoleacetic acid excretion. The serum neuron-specific enolase proved a reliable marker for both response and progression. In the one patient progressive after 3 months, a dose increment to 10 MIU was without effect. In patients initially not progressing or responding to 5 MIU, escalation to 10 MIU had a short lasting beneficial effect in three cases. The radiological characteristics and the kinetics of these responses are compatible with an anti-angiogenic effect of IFN. This study of IFN in carcinoid tumors confirms the activity in this disease. Our results demonstrate the necessity of initiating treatment only in radiologically progressive patients and continuing this treatment until progression. We feel that currently the activity of IFN in metastatic carcinoid tumors compares favorably with that of systemic chemotherapy in patients with progressive disease.