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We report on a rare case of foot and ankle clonus as the initial presentation of progressive multifocal leukoencephalopathy in a young patient with no known history of HIV or AIDS and no significant past medical or social history. The patient came to the emergency department with a chief complaint of muscle spasms in his lower extremities and unsteadiness in gait. The patient was diagnosed as having bilateral ankle clonus. Work-up revealed an absolute lymphocyte CD4+ count of 18, an HIV viral load of 1,690,000, and a positive John Cunningham virus polymerase chain reaction in the cerebral spinal fluid, indicating that the patient had progressive multifocal leukoencephalopathy and AIDS. The diagnosis of progressive multifocal leukoencephalopathy should be in the foot and ankle surgeon's differential diagnosis when a patient presents with neurological symptoms in the lower extremities.