The majority of patients with von Willebrand disease (VWD) have a mild bleeding tendency that primarily involves mucosal bleeding. Some patients with the disorder, however, have severe episodes of mucosal or joint bleeding that can hamper daily activities and lead to significant joint impairment. Experience in the setting of severe hemophilia has shown the feasibility and benefits of prophylactic treatment to prevent bleeding and development of arthropathy. This approach also needs to be evaluated in patients with VWD who require repetitive treatment for bleeding episodes. Data from a series of 35 patients (with VWD types 3, 2A, 2B, and 1) who have received long-term prophylaxis at Malmo University Hospital and Karolinska University Hospital in Stockholm, Sweden, have demonstrated a substantial reduction of bleeding episodes since initiation of treatment. Patients who began prophylaxis at a young age (younger than 5 years) to prevent nose and mouth bleeds have had no joint bleeds and have no clinical signs of arthropathy. Treatment has been safe, with no cases of thrombosis, and no viral transmission among patients who received virus-attenuated von Willebrand factor-containing factor VIII concentrate. These data thus suggest that long-term prophylaxis is warranted in the majority of patients with type 3 VWD and in other subtypes with severe bleeding tendencies, and that such an approach may help in the avoidance of joint disease if started early. More clinical data and controlled trials are needed in order to formulate recommendations for prophylaxis in patients with VWD.