The clinical course of cryoglobulinemic syndrome (CS) is usually slow; however, fast aggravations have been frequently reported in recent years. In these cases vasculitic ischemic tissue damage accounts for glomerular involvement, neuropathy, cutaneous ulcers, ischemic heart disease, lung or jejunal impairment and stroke. Other critical events in CS may be represented by sepsis, liver ... [Show full abstract] insufficiency, hepatocellular carcinoma and non-Hodgkin's lymphomas. Sometimes emergency can not be controlled and the evolution is fatal. Long-term follow up, emergency outcome and cause of death have not been considered in controlled studies, in large series. Here we report a 53-year old woman affected by IgG-IgMk type II HCV-related mixed cryoglobulinemia, who presented several critical events over the course of the disease, which required therapeutical emergency interventions. The latter consisted of plasma exchange, cytotoxic agents, corticosteroids, intravenous immunoglobulin, antihypertensive drugs, antibiotics, and rituximab. Eventually no therapy was effective and the patient died from a catastrophic-like syndrome. This case is relevant because it enables us to consider some important steps in the treatment of emergency in CS.