Interferon-alpha (IFN-alpha) therapy is frequently associated with significant fatigue, which is often the dominant dose-limiting side effect. The fatigue associated with IFN-alpha therapy is usually dose related, worsens with continued therapy, and is associated with significant depression. Although the direct cause of IFN-alpha-induced fatigue is unknown, it is possible that neuromuscular fatigue, similar to that observed in patients with postpolio syndrome, is one component of this syndrome. The induction of proinflammatory cytokines observed in patients treated with IFN-alpha is consistent with a possible mechanism of neuromuscular pathology that could manifest as fatigue. Further research using established techniques for the study of neuromuscular fatigue is needed to test this hypothesis. Understanding the etiology of IFN-alpha-induced fatigue is the first step toward developing effective therapeutic interventions. Nonpharmacologic interventions for fatigue have begun to be seriously evaluated in cancer patients and patients receiving IFN-alpha therapy. Pharmacologic interventions for neuromuscular fatigue also are being investigated.