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Abstract Background Selective plasma exchange (SePE) is a new simple plasma exchange (PE) modality that enables removal of small and medium-sized molecules without removing larger substances such as coagulation factors. In this study, we examined the efficacy of SePE for removal of isoagglutinins in pre-transplant desensitization for ABO-incompatible (ABOi) kidney transplantation. Materials and methods A case series study was performed in 15 ABOi kidney transplant recipients (KTRs) who underwent SePE alone (7 cases) and SePE in combination with double-filtration plasmapheresis or simple plasma exchange (8 cases). The target processed plasma volume (PV) was set at 2 PV, and 5% albumin solution was used as the substitution fluid in all SePE sessions. Changes in isoagglutinin titers (IgG and IgM) and serum IgG, IgM, and fibrinogen levels were examined. We also compared the decrease in isoagglutinin titers between SePE and conventional methods (PE and double-filtration plasmapheresis). Results A total of 29 sessions of SePE were performed in the 15 KTRs. Isoagglutinin titers were controlled to ≤ 1:16 in all patients except for 2 with high isoagglutinin titers, and there were no cases of antibody-mediated rejection. SePE led to a median twofold decrease in isoagglutinin titers (IgG and IgM), with median IgG, IgM, and fibrinogen removal rates of 64.2, 11.7, and 25.5%, respectively. Side effects occurred in only 4 of the 29 sessions. Neither titer decreased after SePE in 30% of the sessions. However, the reductions in isoagglutinin titers in patients undergoing SePE were significantly less than those in patients treated with conventional methods. Conclusion Because SePE is less efficient in removing isoagglutinins compared to conventional methods, the use of SePE alone should be limited to patients with low isoagglutinin titers, and SePE in combination with conventional methods should be used for patients with high isoagglutinin titers. SePE may be a useful treatment option, if applied in appropriate cases, due to its lower cost (about half the price of PE using fresh frozen plasma in Japan) and fewer side effects. However, care is required because about 25% of fibrinogen is removed during SePE.