BK virus nephropathy (BKVN) is increasingly recognized as a major cause of renal allograft failure. Recent reports demonstrate that prompt reduction of immunosuppression upon detection of persistent viremia can be associated with resolution of viremia, with minimal risk of acute rejection (AR). However, these experiences in general have occurred in centers with low baseline risks of AR. It is possible that a finer balance between overimmunosuppression and the risk of AR may exist in centers that routinely transplant patients with higher risk of AR. Thus the risk/benefit of this strategy may be altered in these centers. We report a case of antibody-mediated rejection that followed reduction of immunosuppression for BKVN diagnosed more than 3 months after the onset of viremia. This rejection episode resulted in a greater decrease in graft function than the initial BKVN episode. Issues relevant to the management of these patients are discussed, including the need for improved immune monitoring assays to determine more accurately the balance between infection and rejection.