Humoral rejection processes may lead to allograft injury and subsequent dysfunction. Today, only one B‐cell‐specific agent is in clinical use and the effects of standard and new immunosuppressant substances on B‐cell activation and function are not fully clarified. The impact of sotrastaurin, mycophenolic acid and everolimus on human B‐lymphocyte function was assessed by analysing proliferation, apoptosis, CD80/CD86 expression and immunoglobulin and IL‐10 production in primary stimulated B cells. In addition, B‐cell co‐cultures with pre‐activated T cells were performed to evaluate the effect of the different immunosuppressive agents on T‐cell‐dependent immunoglobulin production. Sotrastaurin did not inhibit B‐cell proliferation, CD80/CD86 expression, and IgG production and had only minor effects on IgM levels at the highest concentration administered. In contrast, mycophenolic acid and everolimus had strong effects on all B‐cell functions in a dose‐dependent manner. All immunosuppressive agents caused decreased immunoglobulin levels in T‐cell‐dependent B‐cell cultures. The data provided here suggest that mycophenolic acid and everolimus, but not sotrastaurin, are potent inhibitors of human B‐lymphocyte function and activation.