Severe type II essential mixed cryoglobulinemia (EMC) bears a poor prognosis. Treatment with corticosteroids and/or cytotoxic drugs infrequently results in long-term remissions, and is associated with significant toxicity. We conducted a prospective study with interferon (IFN) in 21 patients with severe type II EMC unresponsive to immunosuppressive regimens. They were treated with recombinant IFN-alpha 2a (18 patients) or with natural IFN-beta (three patients), alone, at a dosage of 3 megaunits (MU)/d for 3 months, followed by 3 MU every other day as maintenance. We observed 11 complete remissions, five partial remissions, and five minor responses. Of 16 patients observed for more than 1 year, 11 remained in remission for 14 to 40 months; five of them remained in complete remission for 18 to 40 months after withdrawal of treatment. Four patients discontinued treatment because of side effects. In four patients who relapsed while on maintenance therapy with recombinant IFN-alpha 2a, remission could be reinduced by treatment with natural IFN-alpha. The response rate of 77% achieved in this study prompts the use of IFN-alpha as a first-choice drug for type II EMC.