Cryoglobulins are immunoglobulins (Ig) that precipitate when serum is incubated at temperatures lower than 37 C. The existence of circulating cryoglobulins (cryoglobulinemia) is not always related to the presence of symptomatology, and the term “cryoglobulinemic syndrome” is used when patients present clinical manifestations (44). In 1933, Wintrobe and Buell (55) described cryoprecipitation as a laboratory phenomenon. In 1966, Meltzer and Franklin (27) described the typical clinical symptoms associated with cryoglobulinemia, particularly the triad of purpura, arthralgia, and weakness. In 1974, Brouet et al (7) classified cryoglobulins into 3 types: Type I cryoglobulins were those composed of single monoclonal immunoglobulins, and types II and III were those formed by monoclonal (type II) or polyclonal (type III) IgM with rheumatoid factor activity plus the corresponding antigen (usually polyclonal IgG). For this reason, types II and III are classically referred to as “mixed cryoglobulinemia.” Recently, new types of cryoglobulins have been described (41). Cryoglobulins have been observed in a wide variety of diseases, including malignancies, infections, and systemic autoimmune diseases (17, 40). When there is no demonstrable underlying disease, the condition is called “essential cryoglobulinemia.” Since the initial report (36) in 1990 of the association between cryoglobulinemia and hepatitis C virus (HCV) infection, it has become clear that most cases of socalled essential cryoglobulinemia are in fact associated with HCV infection. This has led to important changes in the etiology, classification, and treatment of cryoglobulinemia in the last 10 years. Several studies have analyzed cryoglobulinemia in patients with HCV infection, but studies performed in groups of patients covering all etiologies of cryoglobulinemia are scarce (7, 14, 17, 19, 30). In this study, we analyzed the etiology, clinical manifestations, and immunologic features of a large series of consecutive patients with cryoglobulinemia from a single center (Hospital Clinic, Barcelona, Spain).