OBJECTIVE: To evaluate the effect of recombinant human deoxyribonuclease I (rhDNase) in shortening the length of the hospitalization and improving the chest radiographs (CXRs) in hospitalized infants with respiratory syncytial virus (RSV) infection as a result of its mucolytic properties. METHODS: Randomized, double-blind, placebo-controlled investigation of 75 patients with RSV bronchiolitis. The study was conducted at the University of Michigan Medical Center and St. Joseph Mercy Hospital, both in Ann Arbor, MI. RESULTS: The respiratory rate, wheezing, and retraction difference scores, obtained by subtracting the hospital discharge score from the corresponding hospital admission score, show no difference between the two groups, but the CXR difference scores show that the rhDNase group improved by 0.46 while the placebo group worsened by 0.60 (p < 0.001). Analysis of covariance for the hospital discharge CXR score after adjusting for the hospital admission score for both groups was done. There was a difference in scores between the two groups, with adjusted mean for the study group of 2.03, and 2.76 for the placebo group (p < 0.001). Paired t test statistics in each of the two groups were computed. For the placebo group, the mean increase of 0.60 was significant (p = 0.02), and the mean decrease of 0.46 for the rhDNase group was also significant (p = 0.02). A one-way analysis of covariance with the hospital discharge CXR scores as the dependent variable and the hospital admission score as the covariate showed that there was a significant difference between the groups (p = 0.01). CONCLUSION: In patients with RSV bronchiolitis, there was significant improvement in the CXRs with the use of rhDNase compared to significant worsening in the placebo group. To our knowledge, this is the first report of the use of rhDNase to treat RSV bronchiolitis.