This study describes the response to therapeutic plasma exchange in a 60-year-old man with Waldenstrom's macroglobulinemia who developed a clinically severe bleeding disorder with laboratory features characteristic of acquired von Willebrand's disease. The patient's plasma levels of factor VIII coagulant activity, von Willebrand's factor antigen, and ristocetin cofactor activity were all less than 15 percent of normal, and the bleeding time was more than 20 minutes. In vitro studies did not demonstrate an inhibitor to factor VIII/von Willebrand factor, nor was a precipitating antibody to von Willebrand's factor antigen found in the patient's plasma. Neither infusions of cryoprecipitate nor combination chemotherapy corrected the clinical or laboratory abnormalities. In contrast, plasma exchange corrected the in vitro coagulation abnormalities and was effective in preventing surgical hemorrhage and controlling severe mucosal bleeding on 11 separate occasions. The current case demonstrates that the clinical and laboratory abnormalities in a patient with acquired von Willebrand's disease can be corrected completely by plasma exchange; it is recommended therefore that plasma exchange be considered as a mode of therapy in symptomatic patients with this disorder.