Cytomegalovirus (CMV) polyradiculopathy in human immunodeficiency virus–infected patients is an increasingly rare disease given the widespread availability of effective antiretroviral therapy. Here, we describe a case of CMV polyradiculopathy in a man following the initiation of antiretrovirals. The patient presented with a 2-week history of rapidly progressing bilateral lower extremity weakness resulting in paraplegia; he was diagnosed with CMV polyradiculopathy based on cerebrospinal fluid and magnetic resonance imaging findings. Treatment with ganciclovir, foscarnet, and antiretroviral therapy resulted in rapid reduction of CMV viral load in cerebrospinal fluid and halting of disease progression. Six months after presentation, the patient continues to show improvement in lower extremity strength and has regained the ability to ambulate without assistance for short distances.