AbstractIntroductionTherapeutic plasma exchange (TPE) has been developed more than 100 years ago in an animal model and adapted to humans 30 years later. Since then, the TPE research on animal models is lacking, mainly due to difficulties raised by the scaling of the plasmapheresis unit so that the animal's cardiovascular parameters are not considerably affected.MethodsThe system concept of a novel TPE device with continuous hemodynamic monitoring in small rodent models has been used.ResultsA continuum TPE unit for rats has been developed, able to produce up to 95% plasma exchange rate without any TPE‐related hemodynamic impairment, monitored up to 35 days after the procedure.ConclusionThe TPE unit for rats was able to produce 95% plasma exchange rate in non‐anesthetized animals, enabling a full translation of the human TPE into an animal model. The newly developed plasmapheresis unit enable a wide range of more accurate preclinical evaluation, with cardiac parameters monitoring, using small rodents in awaken state.