- Aim The aims of this pilot study were to determine safety, tolerability (primary outcome) and efficacy (secondary outcome) of high-dose inhaled nitric oxide for the treatment of infants with moderately severe bronchiolitis. Methods This was a pilot, double-blinded, randomized controlled study (phase IIa). Intermittent inhalations of nitric oxide 160 ppm for 30 min or oxygen/air (control) were given 5 times/day to hospitalized infants (2–11 months) with acute bronchiolitis. Oxygen saturation, methemoglobin, and nitric dioxide (NO2) levels and vital signs were monitored. Results Forty-three infants were enrolled. Baseline characteristics were comparable in both study groups. Mean clinical score, comprised of four components: respiratory rate, use of accessory muscles, wheezes and crackles, and % room-air oxygen saturation, was 7.86 (±1.1) and 8.09 (±1.2) in the NO and control groups, respectively, consistent with moderate severity. The overall frequency of adverse events was similar between the groups. Repeated nitric oxide inhalations did not result in increased inhaled NO2 levels or cumulative effect on methemoglobin levels. Secondary outcomes of efficacy were measured by length of hospitalization (LOS) in hours: LOS did not differ between groups. However, in a post-hoc analysis of a subgroup of infants hospitalized for >24 h (n = 24), the median LOS was shorter in the nitric oxide (41.9 h) than in the control group (62.5 h) (P = 0.014). Conclusion Our study was unable to detect a difference in side effects using intermittent high-dose nitric-oxide inhalation or supportive treatment alone, in infants with moderate bronchiolitis. Preliminary efficacy outcomes are encouraging.