Interferon-a (IFN-α) has potential dose-limiting neurotoxic side effects when used in cancer therapy. The nature of this neurotoxicity is speculative, and there is no definitive treatment. Because animal studies suggest that IFN-αacts at opioid receptor sites, we gave naltrexone, a long-acting opioid antagonist, to 9 patients who had hematological malignancies and who suffered from IFN-αside effects. Seven of these patients experienced complete or moderate relief of side effects. Five of the patients tested before and during naltrexone treatment showed improvement of cognitive functioning. Two patients could not tolerate naltrexone side effects. This study suggests an intervention against IFN-αside effects and provides support for the role of opioid receptor interaction in IFN-αneurotoxicity.