Objective. To assess the therapeutic effects of breathing a low-density gas mixture (heliox: 70% helium and 30% oxygen) in infants with bronchiolitis. Design. Prospective, interventional, comparative study. Setting. A pediatric intensive care unit (PICU) in a tertiary care, teaching hospital. Patients. Thirty-eight infants, 1 month to 2 years old, consecutively admitted to the PICU for treatment of moderate-to-severe acute respiratory syncytial virus bronchiolitis. Interventions. The first 19 patients were enrolled as the control group and received supportive care and nebulized epinephrine. In the next 19 patients, heliox therapy was added through a nonrebreather reservoir face mask. Measurements and Outcomes. Respiratory distress score, respiratory rate, heart rate, end-tidal CO2 (etCO2), and pulse oximetry oxygen saturation (satO2) values were recorded at baseline and at regular intervals. Data obtained during the first 4 hours were analyzed for comparison purposes. Demographic data, age, time elapsed from the start of the symptoms to the admission to PICU, length of stay in PICU (PICU-LOS), and duration of heliox therapy were also collected for each patient. Reductions in clinical scores and PICU-LOS were considered primary outcomes. Main Results. At baseline, the heliox and control groups had similar age (5.5 ± 3.1 vs 5.9 ± 3 months), previous length of course (47.3 ± 19.3 vs 45.4 ± 18.6 hours), clinical score (6.7 ± 1.1 vs 6.6 ± 1), heart rate (160 ± 24 vs 165 ± 20 beats per minute), respiratory rate (64 ± 7 vs 61 ± 7 respirations per minute), satO2 (91 ± 2.3 vs 91 ± 2.5%), and etCO2 (34 ± 7 vs 33 ± 6 mm Hg). Clinical score, heart rate, respiratory rate, and satO2 improved during the study in both groups. After 1 hour, the improvement in clinical score was significantly higher in the heliox group than in the control group (3.6 ± 1.16 vs 5.5 ± 0.89), and these differences continued to be significant at the end of the observation period (2.39 ± 0.69 and 4.07 ± 0.96, respectively), with a total average decrease in the score of 4.2 points in the heliox group versus 2.5 points in the control group. Heart and respiratory rates were also significantly lower in the heliox group compared with the control group after 1 hour and stayed lower throughout the rest of the study period. No changes were noted either in satO2 between groups or in etCO2 within or between groups throughout the study. Mean duration of heliox administration was 53 ± 24 hours (range: 24–112 hours) and no adverse effects were detected. PICU-LOS was significantly shorter in the heliox group (3.5 ± 1.1 days) than in the control group (5.4 ± 1.6 days). Conclusions. In infants with moderate-to-severe respiratory syncytial virus bronchiolitis, heliox therapy enhanced their clinical respiratory status, according to the marked improvement in their clinical scores and the reduction of the accompanying tachycardia and tachypnea. This beneficial response occurred within the first hour of its administration and was maintained as long as heliox therapy continued. In addition, PICU-LOS was reduced in heliox-treated patients. Long-term prospective studies are required to corroborate these findings and to establish the proper place of heliox in the therapeutic schedule of bronchiolitis.