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Background: Therapeutic plasma exchange (TPE) is either performed using a highly permeable filter with standard multifunctional renal replacement equipment (mTPE) or a centrifugation device (cTPE). Although both techniques are well established in clinical practice, performance of these two modes of TPE was never compared in a prospective randomized fashion. Thus we aimed to compare two commercially available therapeutic apheresis systems: mTPE (Octonova with Plasmaflo filter) and cTPE (Spectra Optia apheresis system)., Methods: Twenty-one patients (age 51.6 ± 13.5 years; 10 F/11 M; BMI 25.1 ± 5.0 kg/m(2)) were enrolled in this randomized, prospective, paired, crossover study performed in the Hannover Medical School, Germany. First treatment (either mTPE or cTPE) was chosen by an online randomization list. The primary endpoints were plasma removal efficiency with 1.2× of the total plasma volume exchanged. Secondary endpoints were total amount of plasma substances removed, such as IgG and fibrinogen. Further, the treatment effect on platelet count and complications were evaluated., Results: Despite a comparable volume of the processed plasma, mTPE treatment time was 10.5 % longer than cTPE treatment time (p < 0.05), resulting in a 10 % lower plasma removal rate of the mTPE treatment. Both treatments were comparable in terms of decrease in median (IQR) IgG [pre-mTPE 5.34 (3.48-8.37), post-mTPE 1.96 (1.43-2.84) g/L; pre-cTPE 5.88 (3.42-8.84), post-cTPE 1.89 (1.21-3.52) g/L]. Also the median (IQR) amount of IgG removed in mTPE [13.14 (7.42-16.10) g] was not different from the cTPE treatment [9.30 (6.26-15.69) g]. This was also true for IgM removal. Platelet loss during mTPE was nearly twice as much as with cTPE (15 ± 9 versus 7 ± 9 %, p < 0.05)., Conclusion: Although the centrifugal procedures were conducted using flow rates that could easily be obtained using peripheral access, plasma removal efficiency was significantly higher and treatment time was significantly lower in cTPE as compared to mTPE. Despite this lower treatment time, the decline in markers of procedure efficacy was comparable. Especially in centers performing many procedures per year, cTPE in contrast to mTPE can reduce treatment time without compromising treatment efficacy.