Mixed cryoglobulinemia is characterized by a wide spectrum of manifestations that may vary from mild symptoms (such as purpura, arthralgias, and Raynaud phenomenon) to life-threatening conditions (such as acute abdomen, hyperviscosity syndrome, and renal involvement). Hepatitis C virus infection is considered the principal trigger of the disease. Therefore, the treatment not only should be tailored to the prevailing symptom but also take into account the presence of a chronic, often smoldering infection. Symptomatic therapies are to be used in cases of minor clinical manifestations and aggressive modalities in cases of life-threatening conditions. The use of aggressive cytotoxic regimens should actually be stopped and every potentially immunosuppressive drug should be used with caution. Antiviral medications are used with growing frequency. To date, a few small trials with interferon-alpha alone or in combination with ribavirin in mixed cryoglobulinemia have been conducted. This overview deals with the current approach to the management of mixed cryoglobulinemia, focusing in particular on antiviral treatment in hepatitis C virus infection with or without mixed cryoglobulinemia.