Detection of oligomeric alpha-synuclein (o-alpha-Syn) in red blood cells (RBCs) has been shown to be promising in diagnosing Parkinson's disease and other synucleinopathies. However, if RBC o-alpha-Syn derive from plasma and can reflect changes of plasma o-alpha-Syn remains unclear. In this study, synthetic o-alpha-Syn was intravenously injected into mice and dynamic changes in plasma and RBC o-alpha-Syn levels were investigated. Injection of o-alpha-Syn induced a temporary increase in plasma o-alpha-Syn levels, which then decreased to a relatively stable level. In contrast, levels of RBC o-alpha-Syn increased steadily and significantly. Besides, alpha-Syn-immunoreactive particles were observed in RBCs of the injected mice, suggesting that RBCs can actively take up and enrich o-alpha-Syn from plasma. Moreover, incubation of o-alpha-Syn with isolated RBCs at concentrations lower than those of endogenous o-alpha-Syn led to a time- and concentration-dependent o-alpha-Syn elevation in RBCs, which was impaired by lowering the temperature and treatment with proteinase K. The o-alpha-Syn accumulation in RBCs was also inhibited by specific inhibitors of receptor-dependent endocytosis, including dynamin- and clathrin-dependent endocytosis. The above results suggest that plasma o-alpha-Syn can be actively transported into RBCs via receptor-dependent endocytic pathways.