Cold agglutinin disease is a form of direct, extravascular, antiglobulin-positive hemolysis. In vivo, immunoglobulin (Ig) M fixes complement molecules to the red cell membrane. Successive passages through the mononuclear phagocyte system result in loss of red cell membrane. The resultant spherocytes lose resiliency and are ultimately lost from the circulation extravascularly. The high concentration of complement molecules on the red cell surfaces makes this syndrome resistant to the standard therapies for immune-mediated hemolysis. Rituximab has been reported to reduce the severity of hemolysis. Type II cryoglobulins are composed of a monoclonal IgM and a polyclonal IgG. These complexes have rheumatoid factor activity and can produce immune-complex vasculitis. The target organs are the skin, nerves, kidney, liver, and joints. More than 80% of patients have evidence of hepatitis C infection. Interferon and interferon plus ribavirin have been shown to produce serologic responses. When vasculitis is active, corticosteroids are often required to permit healing of ulcers in the skin or to treat the membranoproliferative glomerulonephritis that is seen, thereby preventing loss of renal function. Rituximab therapy has been found to be effective in mixed cryoglobulinemia, with decreases in cryoglobulin values and improvement in complement values.