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Belatacept is a novel T-cell costimulation blockade agent that has unresolved controversy in lung transplant recipients. Belatacept has been recognized as a calcineurin sparing agent for solid organ transplant recipients after reported success in renal transplant patients, despite limited evidence in other transplant recipients. We present the first case of a lung transplant recipient receiving Belatacept, in combination with low dose calcineurin inhibitor, who developed progressive multifocal leukoencephalopathy. While Belatacept without calcineurin inhibitor has been associated with increased risk of acute rejection in solid organ transplant recipients, its infectious risk profile in combination with calcineurin inhibitor remains unclear.