Enteroviruses usually cause self-limited disease that, although associated with high morbidity, is rarely fatal. In certain patient populations, however, the enteroviruses may cause potentially life-threatening infections. Pleconaril is a novel compound that integrates into the capsid of picornaviruses, including enteroviruses and rhinoviruses, preventing the virus from attaching to cellular receptors and uncoating to release RNA into the cell. Pleconaril was used on a compassionate-release basis to treat patients with potentially life-threatening enterovirus infections, and for 38 of these patients sufficient follow-up data were available for determining responses to therapy. Response was evaluated in 4 categories: clinical, virological, laboratory, and radiological. Most patients (28 [78%] of 36), including 12 of 16 with chronic enterovirus meningoencephalitis, were judged to have a clinical response temporally associated with pleconaril therapy. Similarly, nearly all patients whose virological responses (12 [92%] of 13), laboratory responses (14 [88%] of 16), and radiological responses (3 [60%] of 5) could be evaluated were judged to have responded favorably to a course of pleconaril treatment. Adverse effects were minimal and the drug was generally well-tolerated.