By contrast to cryoglobulinemic vasculitis, polyarteritis nodosa associated with hepatitis C virus (HCV) infection is rare and still a controversial entity. The best treatment for this condition is not established. Cases reported in the literature have been treated with various combinations of corticosteroids, antiviral therapy, and immunosuppressants. We report a case of severe life-threatening HCV-associated polyarteritis nodosa successfully treated with rituximab and a short course of corticosteroids without antiviral therapy. This case, along with recently published data, emphasizes the value of B-cell–targeted therapy in this unusual form of HCV-associated vasculitis.