Neurological syndromes attributed to cytomegalovirus (CMV) in patients infected with human immunodeficiency virus (HIV) include encephalitis, myelitis, and peripheral neuropathy. More recently, polyradiculopathy due to CMV has been described. We review the literature and describe two patients with CMV polyradiculopathy whose conditions improved only after prolonged therapy with ganciclovir. Patients typically are young men who are severely immunocompromised and have had other opportunistic infections. The syndrome is characterized by subacute onset of leg weakness and numbness progressing to paraparesis or paraplegia. Bladder dysfunction is common. In many patients, CMV may be identified elsewhere; concomitant retinitis is common and often subclinical. Laboratory studies commonly show an increased number of neutrophils in CSF and hypoglycorrhachia. Electromyography and nerve conduction studies support the diagnosis. Imaging studies may be most useful to exclude spinal lesions. Without treatment prognosis is poor. Survival time is improved and symptoms often abate, sometimes dramatically, with ganciclovir therapy. Improvement of conditions may be rapid but can take months, as illustrated by these two cases. Once initiated, ganciclovir should be administered indefinitely to patients with CMV polyradiculopathy.