Current immunosuppressive regimens consisting of steroids, a calcineurin-inhibitor, and mycophenolate Evofosfamide mofetil inhibit B-cell function directly due to inhibition of their proliferation and indirectly via the inhibition of T-cell help. B cells can also be selectively depleted by rituximab, an anti-CD20 monoclonal antibody. RTX is successfully used in the treatment of B-cell malignancies and autoimmune disorders mediated by T and B cells. Although the major target of RTX-based treatment was to reduce the levels of circulating autoantibodies, additional B-cell functions may be affected, such as antigen presentation and cytokine production. Furthermore induction of regulatory T cells was reported after RTX treatment in patients with lupus nephritis. Therefore, next to its effect on B cells, RTX might decrease the chance of rejection after transplantation by affecting the T-cell compartment. Remarkably little is known about the effects of the currently used immunosuppressive strategies on the phenotype and function of T and B cells during the course after renal transplantation. Advancements in multiparameter flow cytometry have made it possible to analyze the effects of immunosuppressive agents on various T- and B-cell subsets in more detail. We had the opportunity to study the effects of standard immunosuppression, with or without the addition of RTX induction therapy on the phenotype and function of T and B cells over time in renal transplant recipients participating in a randomized placebo-controlled trial, studying the efficacy and safety of RTX added to standard immunosuppression. To avoid bias by other immunological events as much as possible, we analyzed only Cytomegalovirus seronegative patients who received a kidney from a CMV seronegative donor, did not experience a rejection episode, and were not treated with additional immunosuppressive drugs during the follow-up period. Despite the extensive clinical experience with currently used immunosuppressive drug regimens, there are limited data available regarding their effects on the peripheral lymphocyte compartment after kidney transplantation. One study describes the effects of cyclosporine, MMF, steroids, and anti-CD25 monoclonal antibody therapy on T and B cells of mainly CMV seropositive renal transplant recipients at 6, 24, and 60 months after transplantation. This therapy resulted in an increased percentage of CD4+ CD25+ TREGS and CD27+ memory B cells in renal transplant recipients compared to healthy donors, but the data were not compared with pre-transplant levels. In contrast, we performed a longitudinal analysis of T- and B-cell phenotype and function in CMV seronegative patients who received a kidney from a CMV seronegative donor and did not experience a rejection episode up to 24 months after transplantation. In this homogeneous patient population, not affected by major immunological events, we showed that treatment with the combination of tacrolimus, MMF and steroids had no effects on the total number of T and B cells. Nevertheless, these patients had a higher proportion of central memory CD4+ and CD8+ T cells at 3 months after transplantation compared to pre-transplant levels. Interestingly, the triple drug immunosuppression resulted in a shift toward a more memory-like phenotype in the B-cell population.