This is the first study aiming to assess the effects of heliox in combination with nasal continuous positive airway pressure (Hx-nCPAP) as a rescue treatment in infants with refractory acute bronchiolitis. Fifteen out of 78 infants with acute bronchiolitis consecutively admitted to PICU fulfilled the inclusion criteria: clinical score>or=5 or arterial oxygen saturation (SatO2)<or=92% or PCO2>50 mmHg, despite supportive therapy, nebulized L-epinephrine, and heliox therapy through non-rebreathing reservoir facemask. Hx-nCPAP was added as a rescue treatment. Baseline mean (standard deviation) values were: clinical score of 7.4 (1.2) points; PCO2 of 63.8 (12) mmHg; respiratory rate (RR) of 66.4 (9.9); and SatO2 of 88.6 (4.7)%. Clinical score, PCO2, RR and SatO2 improved during the study time (P<0.05). After 1 h the mean clinical score decreased by 1.5 points, with a total average decrease of 3.5 points at the end of the study period. The mean PCO2 diminished by 9 and 25 mmHg, after 1 and 48 h, respectively. The mean RR decreased 13 rpm after 1 h and 30 rpm after 48 h. The Hx-nCPAP total duration ranged from 2 to 14 days. Only one patient required endotracheal intubation. No adverse effects were detected. All patients recovered fully. In conclusion, Hx-nCPAP improved the clinical score, decreased the tachypnea and enhanced the CO2 elimination of infants with refractory acute bronchiolitis within 1h of administration, in a safe and non-invasive manner. Hx-nCPAP might reduce the need for endotracheal intubation. Further studies are needed.