In order to study the long-term immunogenicity of interferon-alpha 2c (Berofor) in cancer patients, serum was collected starting in 1983 from study patients with various proliferative diseases who received interferon-alpha 2c at different doses, according to different schedules, and via different routes. A total of 1992 samples were tested for the presence of anti-interferon-alpha 2c antibodies. Due to long-term interferon-alpha 2c treatment, 346 patients were eligible for induction of neutralizing anti-interferon antibodies over a treatment period of 2-52 months. Most patients were treated for longer than 6 months. Of the 346 patients, three patients (0.87%) exhibited measurable titers of neutralizing antibodies following therapy with interferon-alpha 2c. One hundred and sixty-three patients suffered from non-Hodgkin lymphomas, leukemias, and preleukemias. One patient with chronic myeloid leukemia experienced antibody induction under therapy. The other 183 patients had solid tumors. Two of them reacted with antibody production. All titers were very low (1:12, 1:8, and 1:64). Compared with figures reported for other interferon-alpha preparations, the propensity of interferon-alpha 2c to induce neutralizing antibodies seems to be very low. This property might be related to arginines occurring as critical residues in positions 23 and 34 of the interferon-alpha 2c molecule.