Interferon-alpha (IFN-alpha) is well established in the treatment of neuroendocrine carcinomas (NEC). Treatment is accompanied by fatigue and flu-like symptoms. In patients with chronic hepatitis C, pegylated IFN (PEGIFN) leads to improved antiviral efficacy and good tolerability. Our aim was to assess the efficacy and tolerability of PEG-IFN on the management of patients with well-differentiated NEC of the gastroenteropancreatic system. In 17 patients, the effect of PEG-IFN-alpha2b was studied. After first-line octreotide treatment, IFN-alpha was added at the time of tumor progression. Six patients were switched from conventional IFN-alpha, and 11 patients were IFN naive. Inhibition of tumor growth, including stabilization of disease, occurred in 13 of 17 patients, and biochemical and symptomatic responses were seen in 7 of 10 patients with functionally active tumors. Tolerability of PEG-IFN-alpha2b was much better than that of IFN-alpha. Fatigue occurred in 59% of all patients but was mild in severity. Eleven of thirteen patients who had a benefit remained on therapy for a median time of 20 months (range 6-30 months). PEG-IFN-alpha2b provides symptomatic and antiproliferative efficacy in patients with NEC. Better tolerability of PEG-IFN-alpha2b improved patients' compliance, justifying its use in patients who do not tolerate conventional IFN-alpha treatment.