A radioimmunologic technique has been developed to screen sera of persons receiving human alpha-2 interferon for the presence of specific antibodies to alpha-2 interferon. The method is sensitive and easy to perform. It tests the ability of the sera to neutralize alpha-2 interferon and prevent the interferon from being detected by an immunoradiometric assay. The results obtained using this technique are in good agreement with an anti-viral, cytopathic effect assay. Using the immunological technique, the sera from more than 1000 individuals who had received different doses of alpha-2 interferon by one or more of various routes of administration were tested. Twenty-five sera representing 14 individuals gave a positive or possibly positive reaction in the assay. Three of the 14 individuals were positive prior to receipt of alpha-2 interferon. Another 3 had reverted to negative when tested a few months later. Of the remaining 8, only 4 developed titers greater than 100 neutralizing units/ml. Hence approximately 1% of the alpha-2 interferon recipients may have produced neutralizing antibodies.