Mixed cryoglobulinemia is a systemic vasculitis with clinical manifestations ranging from the characteristic benign-appearing syndrome of palpable purpura, arthrologies, and fatigue to severe vasculitis involving vital organs. A strong association of the disease with hepatitis C virus infection and the demonstration of the specific concentration of the virus in the cryoglobulins have implicated hepatitis C virus in the etiopathogenesis of the disease. The increase in illicit intravenous drug use in the past 30 years seems to have raised the occurrence in the United States of this once uncommon disease and changed the demographics: there seem to be more male intravenous drug users in their forties with the disease than women without risk factors for hepatitis C virus infection in their fifties and sixties. Pathogenesis, therapy, and the hypothesis on the etiologic role of hepatitis C virus are reviewed, and the implications of recent studies and new concepts for treatment of this often benign-appearing but deceptive and potentially life-threatening disease are discussed.