Type II mixed cryoglobulinemia syndrome (MCsn) is a systemic vasculitis mainly linked to immune complex deposition in several organs and to hepatitis C virus (HCV) infection. Therapeutic strategies can target either the viral trigger HCV if present, or pathogenic events downstream the triggering infection, e.g, the proliferating B-cells directly. Antiviral therapy should be considered as first-line treatment in many HCV-positive patients. However, it may prove ineffective, contraindicated, or poorly tolerated. On the other hand, the other available treatments (such as cytotoxic agents, plasma exchange and steroids) may lead to life-threatening complications and may be difficult to manage in the long term. Given the good safety profile in lymphomas, rituximab (RTX) has been used off-label for numerous patients suffering from a variety of autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus, dermatomyositis/ polymyositis, and anti-neutrophil cytoplasmic antibody (ANCA)-positive vasculitis. Efficacy and safety of RTX in MCsn and in particular in MCsn-related glomerulonephritis was recently described. Based on these results, a multicentre, controlled, randomised, clinical trial is now ongoing to compare RTX versus the best available treatments in some severe MCsn manifestations (i.e. skin ulcers, sensory and/or motor neuropathy and active glomerulonephritis).