Deficiencies in circulating anticoagulant protein C (PC) occur in patients undergoing hematopoietic stem cell transplantation. These deficiencies may predispose to thrombotic and other complications, and may contribute to the morbidity of transplantation. In most patients, PC reaches a nadir 14 days after the preparative regimen and then begins to increase toward normal. However, low PC has been seen months after transplantation. Neither the frequency of, nor risk factors for, this prolonged deficiency are known. We examined 71 adults undergoing stem cell transplantation and found low PC antigen and activity in 21% and 20% of patients, respectively. Low PC at day 100 correlated strongly with low PC pre-chemotherapy (PC antigen, r = 0.69, P < 0.001; PC activity, r = 0.59, P < 0.001). The incidence of deficiency of PC at day 100 was lower in patients undergoing peripheral stem cell transplantation compared with patients undergoing autologous BMT (12.5% vs 35%; P = 0.05), although several significant confounding variables exist. We conclude that deficiencies in protein C persist at least 100 days after stem cell transplantation in nearly one quarter of patients undergoing this procedure. Therefore, patients undergoing stem cell transplantation may be at prolonged risk of thrombotic and other complications. Further studies to determine the risk of prolonged deficiency based on stem cell source need to be performed.