Cryoglobulinemic vasculitis (CryoVas) is a small-to-medium vessel systemic vasculitis caused by the deposition of mixed cryoglobulins and immune complexes. Clinical spectrum of CryoVas ranges from mild symptoms to vasculitis involving multiple organs that may progress to more life-threatening ilness. Hepatitis C virus (HCV) chronic infection is the most frequent condition to be assessed in patients with CryoVas. The mortality rate among patients with HCV-associated CryoVas is 3× that of the general population, with a 63% 10-year survival rate. The recent advent of interferon-free direct-acting antivirals (DAAs), which have the potential to induce sustained virological response rates greater than 95%, has dramatically changed the management of chronic HCV infection and HCV-related CryoVas. B-cell depleting strategies, mainly with rituximab, are the main therapeutic option in severe and refractory cases of HCV-associated CryoVas. Despite the progress in the last years on the management of chronic HCV infection, there are still unmet needs regarding therapeutic management of severe and refractory HCV-associated CryoVas.