Desensitization protocols comprising plasmapheresis, IVIGs, and rituximab and/or bortezomib have allowed for successful kidney transplantation in some highly HLA-sensitized patients with end-stage renal disease. However, the optimal combination of these therapies and their proper timing remains entirely unknown. We propose a phased desensitization strategy using rituximab followed by bortezomib as a safer method. There have been reports of patients with persistent B-cell dysfunction even after the completion of rituximab treatment for B-cell lymphomas and autoimmune conditions. To avoid either persistent immune dysfunction or hypogammaglobulinemia, identifying immune recovery via periodic monitoring is prudent before starting additional immunomodulatory therapy with bortezomib. We found that IgM+ CD19+ mature B cells recovered more rapidly, returning to baseline by 6 months, whereas IgM+ CD27+ memory B cells remained low at 2 years after rituximab treatment. Hence, the period after rituximab treatment characterized by the presence of mature B cells but the absence of memory B cells may represent an appropriate therapeutic window for the subsequent bortezomib treatment. Alloantigen-reactive T cells are thought to play a key role in the production of DSA. We evaluated the anti-donor T-cell response by using CFSE-MLR assay. Owing to the continuous administration of CNI and MMF during desensitization, the anti-donor T-cell responses in all the 6 patients were decreased in the CFSE-MLR assay compared with those before desensitization. The effective suppression of alloantigen-reactive T cells might be a prerequisite for successful desensitization for highly sensitized cases. One of the striking findings in this series might be the minimal impact of the phased desensitization protocol on Abs specific for varicella zoster virus and cytomegalovirus despite its remarkable depleting effects on both DSA and non-DSA. Such a differential ability of proteasome inhibition to affect DSA and not Abs against viruses may be due to individual plasma cell activity. It is likely that bortezomib will have a differential effect on plasma cells that produce high amounts of anti-HLA Abs compared with those that produce low amounts of Abs specific for various viruses. In conclusion, the present cases suggest that a phased use of rituximab and bortezomib can safely desensitize highly HLA-sensitized kidney transplant candidates, warranting a further larger scale prospective study.