BACKGROUND: A helium-oxygen gas mixture (heliox) has low gas density and low turbulence and resistance through narrowed airways. The effects of heliox on pulmonary mechanics following severe methacholine-induced bronchospasm were investigated and compared to those of a nitrogen-oxygen gas mixture (nitrox) in an innovative pediatric porcine, independent lung, mechanical ventilation model. RESULTS: All of the lungs showed evidence of severe bronchospasm after methacholine challenge. Prospective definition of 'heliox response' was a 15% or greater improvement in lung function in the lung receiving heliox compared with the matched lung receiving nitrox. Seven out of 10 pigs responded to heliox therapy with respect to resistance and eight out of 10 pigs responded to heliox therapy with respect to compliance and tidal volume (P < 0.03). After crossover from nitrox to heliox, eight out of eight lungs significantly improved with respect to tidal volume, resistance and compliance (P < 0.001). After crossover from heliox to nitrox all eight lungs showed a significant increase in resistance and a significant decrease in tidal volume (P < 0.001). CONCLUSIONS: In a pediatric porcine model of acute, severe methacholine-induced bronchospasm and independent lung mechanical ventilation, administration of heliox improves pulmonary mechanics, gas flow, and ventilation. Administration of heliox should be considered for support of pediatric patients with acute, severe bronchospasm requiring mechanical ventilation through small artificial airways.