Despite the absence of randomized trials, plasmapheresis has consistently demonstrated efficacy in treatment of Waldenström's macroglobulinemia (WM) patients with hyperviscosity syndrome (HVS). This procedure can promptly reverse most clinical manifestations of serum HVS. Early diagnosis is crucial and usually can be made from the funduscopic exam. Serial viscosity measurements can be monitored by the Ostwald tube method which is simple, reproducible, and for which there is substantial clinical correlation. The concept of a symptomatic threshold, whereby each WM patient has a distinct viscosity threshold for the development of HVS, seems valid. Maintaining serum viscosity below each patient's symptomatic threshold effectively prevents recurrent HVS. Plasmapheresis is sometimes necessary as an emergency procedure and is useful maintenance therapy in selected patients. Prophylactic plasmapheresis should be considered in patients at risk for HVS after rituximab therapy. Vigorous plasmapheresis in WM patients with syndromes because of autoreactive immunoglobulin M antibodies requires further study.