Progressive multifocal leukoencephalopathy caused by polyoma JC virus is a rare and severe demyelinating disease of the central nervous system. It occurs in immunocompromised patients and is scarcely reported in liver transplant recipients. Brain biopsy demonstrating demyelination with presence of foamy macrophages, relative preservation of axons, astrogliosis, and typical polyomavirus inclusions in the enlarged oligodendroglial nuclei is essential for diagnosis. Here, we report a case of JC virus-associated progressive multifocal leukoencephalopathy in a living-donor liver transplant recipient who was transplanted for hepatitis C virus-related decompensated cirrhosis. Brain biopsy with immunohistochemistry confirmed the diagnosis of progressive multifocal leukoencephalopathy secondary to JC virus. JC virus related-progressive multifocal leukoencephalopathy is associated with extremely poor prognosis. Awareness and consideration of this entity in liver transplant recipients who present with sudden progressive neurologic manifestations can help in prompt diagnosis and timely treatment.