The discovery of the strong association between hepatitis C virus (HCV) infection and the development of mixed cryoglobulinemia has motivated active testing of antiviral-directed alternative therapies. Several trials have demonstrated that classic cryoglobulinemia-associated manifestations improve with interferon-α (IFNα) treatment. Herein we report on 3 HCV-infected patients with severe cryoglobulinemia-related ischemic manifestations who were closely followed up during IFNα therapy. Clinical evaluations with special attention to ischemic lesions, liver function tests, and cryocrit determinations were serially performed. In addition to prednisone and immunosuppressive agents, the patients received IFNα at 3 × 106 units, 3 times per week for 2 months, 3 months, and 4 months, respectively. In all 3 patients, systemic features improved, liver function results returned to normal, and cryocrit values decreased. However, ischemic lesions became less vascularized and ischemia progressed, leading to transmetatarsal and subcondylar amputation, respectively, in 2 of the patients and fingertip necrosis and ulcer enlargement in the third. Skin biopsies performed before IFNα therapy and after 2 months of IFNα therapy in the third patient showed a significant decrease in subepidermal microvessels. When IFNα was discontinued, the lesions finally healed. Cryoglobulinemia-related ischemic lesions may worsen during IFNα treatment, presumably through a decrease in inflammation-induced angiogenesis. The anti-angiogenic activity of IFNα may delay the appropriate healing of ischemic lesions.