Mixed cryoglobulinemia is a cryoprecipitable immune-complex mediated disease, in which cryoglobulins are type II and III of the immunochemical classification of Brouet. Essential mixed cryoglobulinemia, in opposition to secondary, is characterized by the absence of well-defined underlying disease and clinically it shows the classical triad of Meltzer and Franklin. Several reports point to the frequent, through various, liver involvement in essential-defined mixed cryoglobulinemia. Particularly, the clinical and biological evidence of liver disease is commonly soft, in spite of the common bioptic evidence of persistent or chronic active hepatitis. The problem about which comes first in this association had been widely investigated, including the possible pathogenetic role of hepatotropic viruses. Initially some studies focused attention on hepatitis B virus, but now its importance is de-emphasized because of critical epidemiological review, results of HBV-DNA in cryoprecipitates, electron microscopy data. The recent opportunity of diagnostic tests for hepatitis C virus gave proof of its great importance in apparently essential mixed cryoglobulinemia. In fact, many researches have found a variously high prevalence of anti HCV antibodies and HCV-RNA in serum and cryoprecipitates, with selective concentration in the latter. Alpha interferon treatment has been suggested as first choice drug in the management of HCV related cryoglobulinemia. The mechanism is postulated to be primarily due to its antiviral activity. Up to date optimal dose and treatment period needs to be established.