The effects of interferon-α (IFN-α) on clinical and serologic manifestations of mixed cryoglobulinemia (MC) were investigated by randomized, crossover-controlled trial in 26 patients. The trial alternated 6 months with and 6 months without IFN-α therapy (2 × 10⁶ IU daily for a month, then every other day for 5 months). In 22 patients, pretreatment steroid dosage remained unchanged during the study. Six patients dropped out (three because of side effects), whereas another 20 patients experienced a significant improvement of purpura (P < .02) and serum transaminases (P < .005) during IFN-α treatment. The presence of clinical improvement was supported by the outcome measurements of several immunologic parameters. In particular, serum cryoglobulins were significantly reduced (P < .04) during IFN-α therapy. A rebound phenomenon of clinical and serologic parameters was observed after IFN-α discontinuation. In addition, no variations were recorded during 6 months without therapy. Hepatitis C virus (HCV) RNA was detected in 91 % (20/22) of our MC patients; in 2/13 cases HCV RNA was no longer detectable in serum samples after IFN-α therapy. Thus, IFN-α could be considered as treatment for MC in patients with HCV seropositivity.