Cytomegalovirus (CMV) polyradiculomyelopathy is an uncommon but distinctive clinical syndrome in HIV-infected patients in which ascending motor weakness, areflexia, loss of sphincter control, paresthesias, and varying sensory impairment develop subacutely in association with a polymorphonuclear pleocytosis, increased protein, and hypoglycorrhachia in CSF. Responses to treatment with ganciclovir have varied in reported cases. We report three additional cases: two of these patients responded to treatment and the third was demonstrated to have CMV resistant to ganciclovir. We review other reported cases and identify factors predictive of ganciclovir resistance, which include persistent polymorphonuclear pleocytosis and hypoglycorrhachia on serial CSF studies, and positive CMV cultures from CSF or blood after induction therapy. We conclude that ganciclovir may be an effective therapy for CMV polyradiculomyelopathy, but the presence of these factors, or the development of the syndrome in a patient already being treated with ganciclovir, should prompt consideration of alternative antiviral therapy.