Thrombotic thrombocytopenic purpura (TTP) remains enigmatic from the perspective of its etiology, pathophysiology, and treatment. Once recognized, the accepted standard of care for TTP is daily therapeutic plasma exchange (TPE). However, the diversity in TPE treatment protocols has made comparisons of clinical research between institutions difficult. This study strived to assess the current practice of TPE in order to provide direction for prospective controlled clinical trials. Twenty large apheresis centers within the United States comprising the US TTP ASG responded to a survey to establish the current status of TPE in TTP. A retrospective analysis from data provided by 14 of 20 centers included 115 initial presentations of primary TTP with an overall mortality rate of 10% and relapse rate of 37%. The majority of deaths (58%) occurred within 48 hours of presentation. Variation in therapeutic targets (platelet count [plt] and serum LDH) and the number of plasma volumes exchanged per procedure did not affect the relapse rate. Initial plt and LDH were not predictive of mortality. Response, relapse, and mortality rates with the combination of 5% albumin for the initial 50% of TPE followed by plasma for the final 50% of TPE as replacement were comparable or possibly better than plasma-only replacement strategies. Forty percent of centers routinely used a TPE taper; however, there was no statistical difference in relapse rates comparing the taper and non-taper sub-groups. By controlling for adjunctive modalities such as steroids and anti-platelet agents, it is hoped that future prospective clinical trials may optimize the role of TPE in TTP, minimize patient exposure to blood products and procedures, shorten the clinical course of TTP, and reduce mortality.