Interferon causes profound biological changes when given to patients with cancer and many of these could not be predicted from in vitro or animal model systems. We documented significant changes in hormonal levels for a group of 18 patients who were participants in a Phase I gamma-interferon trial. Adrenocorticotropic hormone, cortisol, and growth hormone were all significantly elevated 2 h after treatment with gamma-interferon, with cortisol and adrenocorticotropic hormone returning to base line by 24 h. A placebo group failed to show this change, suggesting a specific interferon effect. Possible mechanisms for these findings and implications for the use of interferons are discussed.