"Cryoglobulinemia" refers to the presence of cryoglobulins (immunoglobulins that precipitate at variable temperatures < 37 degrees C [98.6 degrees F]) in serum. Monoclonal cryoglobulinemia (type I) involves a single type of monoclonal immunoglobulin, while mixed cryoglobulinemia involves a mixture either of polyclonal immunoglobulin (Ig) G and monoclonal IgM (type II), or of polyclonal IgG and polyclonal IgM (type Ill); both monoclonal and polyclonal IgM have rheumatoid factor activity. Cryoglobulinemia is a unique model of human disease for several reasons: (1) cryoglobulins are detected using a simple technical approach that is based on in vitro laboratory observation of cold precipitation in serum; (2) cryoglobulinemic organ damage may be produced by two different etiopathogenic mechanisms (accumulation of cryoglobulins and autoimmune-mediated vasculitic damage); and (3) cryoglobulinemia is associated with a wide range of etiologies, symptoms, and outcomes, and is considered a disease that combines elements of autoimmune and lymphoproliferative diseases. There are three main broad treatment strategies in cryoglobulinemia-conventional immunosuppression, antiviral treatment, and biologic therapy. Some agents, such as corticosteroids and rituximab, have been successfully used in all types of cryoglobulinemia; however, treatment should be modulated according to the underlying associated disease (chronic viral infections, autoimmune diseases, or cancer), the predominant etiopathogenic damage (vasculitis vs. hyperviscosity), and the severity of internal organ involvement.