BACKGROUND Apheresis is increasingly being applied to collect cells or plasma, even allowing the collection of multiple blood components during one procedure. Although the quality of the cellular and plasma products that are obtained by apheresis have been extensively studied and shown to be of high quality, the impact of apheresis on the red blood cells (RBCs) that are returned to the donor has not been investigated. STUDY DESIGN AND METHODS The effect of the plasma‐ or plateletpheresis procedures by four different devices—MCS+ (Haemonetics), PCS2 (Haemonetics), Trima Accel (Terumo BCT), and Autopheresis‐C (Auto‐C, Fresenius Kabi)—on the RBCs that are returned to the donor was tested in a blinded, prospective trial in a cohort of 25 donors. RESULTS A rheologic analysis of donor RBCs before and after plasma‐ or plateletpheresis showed no differences in outcome. However, a strong increase in hemolysis was found in samples from the Trima Accel devices after plateletpheresis, compared to all other machines tested. Furthermore, an increase in complement deposition on RBCs was seen after all plasmapheresis procedures (MCS+, PCS2, and Auto‐C). Finally, a significant decrease in the expression of the complement‐regulating protein CD59 was seen in all postapheresis samples as well as a significant decrease of the adhesion molecule CD147. CONCLUSION The increase in complement deposition and the decrease in the expression of CD59 suggests that RBC clearance might be enhanced after return to the donor. Possible side effects due to an increase in hemolysis after Trima Accel plateletpheresis should be further investigated.