Polyomavirus nephropathy (PVN) is an emerging medical dilemma in kidney transplantation. Methods to screen before clinical disease are available and early immunosuppression reduction may change the natural history of progression. However, the consequences of an increase in rejection may limit the benefits. In a simulation model a 'screen' versus 'no-screen' strategy was compared. Baseline PVN cumulative incidence was assumed to be 4%. Patients with PVN were modeled to have 4-fold higher risk of graft loss. In the screen strategy, patients positive for blood DNA PCR had their immunosuppression reduced. This pre-emptive change was modeled to reduce progression to overt PVN by 80%. Therapy reduction was associated with a 10% risk of precipitating acute rejection and greater risk of chronic allograft loss. In the baseline case, screening saved 1912 dollars (discounted) and produced 0.020 more quality adjusted life years (QALYs) than not screening. Screening resulted in decreased net QALYs if the false positive viremia rate was >9.5% and the PVN incidence was <2.1%. Much of the cost savings of screening relate to savings from immunosuppression reduction in the screened arm. Screening may well be cost-effective if not cost saving in centers with high PVN rates. There remain significant areas of uncertainty.