Background. Respiratory syncytial virus infection of the upper airways may progress to fatal pneumonia in hematopoietic cell transplant recipients. The safely and efficacy of aerosolized ribavirin in preventing disease progression is unknown. Methods. In a multicenter prospective trial, hematopoietic cell transplant recipients with respiratory syncytial virus infection of the upper airways were randomized to receive ribavirin (2 g 3 times daily) or supportive care for 10 days. The primary end point was progression to radiographically proven pneumonia. Secondary end points included virologically proven respiratory syncytial virus pneumonia, viral load changes, and safety. Results. Fourteen patients were randomized to 1 of 2 treatment arms. The trial was discontinued after 5 years because of slow accrual. Pneumonia at 1 month after randomization occurred in 1 of 9 patients who received ribavirin and in 2 of 5 patients who received supportive care (P = .51); virologically proven respiratory syncytial virus pneumonia occurred in 0 of 9 and 2 of 5 patients, respectively (P = .11). At 10 days after randomization, the average viral load decreased by 0.75 log10 copies/mL in ribavirin recipients, compared with a viral load increase of 1.26 log10 copies/mL in untreated patients (P = .07). No discontinuations of ribavirin therapy because of adverse effects occurred during 84 drug administrations. Rates of adverse events were similar in both groups. Conclusions. Preemptive aerosolized ribavirin treatment appeared to be safe, and trends of decreasing viral load over time were observed. However, proof of efficacy remains elusive in hematopoietic cell transplant recipients. © 2006 by the Infectious Diseases Society of America. All rights reserved.