Alpha interferons at doses of 3-9 MU subcutaneously, three to seven times/week, have been administered to 32 patients with malignant endocrine pancreatic tumors. The objective biochemical response rate was 63 percent with a median duration of 20.5 months. Significant reduction of tumor size was only noticed in 20 percent of the patients. Alpha interferon administered to 111 patients with malignant carcinoid tumors showed objective biochemical responses in 42 percent of the patients with a median duration of 32 months. Another 39 percent of the patients showed stabilization of disease without any further tumor growth. Subjective improvement was noticed in 70 percent of the patients. When survival data are analyzed in patients with malignant carcinoid tumors, the median survival from start of treatment was 80+ months in the group of patients treated with alpha interferon, which should be compared with only eight months in a historical group treated with chemotherapy (streptozotocin plus 5-fluorouracil). The adverse reactions to alpha-interferon treatment are dose-dependent and include, mainly, flu-like symptoms, fatigue, and low-grade weight loss. Autoimmune reactions are noted in about 20 percent of the patients. Patients treated with recombinant alpha interferons might develop neutralizing interferon antibodies (6-27 percent), which abrogate the anti-tumor response. The anti-tumor effect in neuroendocrine tumors includes anti-proliferation, apoptosis, differentiations, and cytotoxic/cytostatic effects. Furthermore, immunomodulation is obtained by increased expression of class I antigens on tumor cells. Four patients also developed antibodies directed against carcinoid tumor cells. Alpha interferons induce several nuclear enzymes such as 2'-5'-A synthetase, p-68 kinase, and Mx-A proteins, which are involved in a downregulation of expression of growth factors, oncogenes, and peptide hormones, leading to anti-proliferation and/or apoptosis. The response to alpha-interferon treatment might be predicted by analysis of the induction of 2'-5'-A synthetase in samples from neuroendocrine tumors. Stimulatory tests of hormone secretion, such as meal stimulation of pancreatic polypeptide secretion or secretin test, clearly demonstrate a normalization during alpha-interferon treatment, which might depend on reduced peptide production and/or secretion but also on eradication of malignant cell clones. In summary, alpha interferons have demonstrated significant anti-tumor effects in patients with malignant neuroendocrine gut and pancreatic tumors. The adverse reactions are dose-dependent and manageable. The anti-tumor effects of alpha interferons are pleiotropic and include several direct effects on tumor cells but also immunomodulation.