To compare the effects of heliox-driven (He 80:O2 20) to air-driven (N 79:O2 21) beta2-agonist aerosol therapy on pulmonary function tests (PFTs) in patients with asthma, a prospective randomized crossover study was undertaken in the asthma clinic of the university-affiliated county hospital in Houston, TX. Thirty-one patients (22 female, age range 18-44) with clinically stable asthma consented. All patients were studied on two different days with both heliox and air as driving gas, therefore serving as their own controls. The PFTs including forced expiratory volume in 1 sec (FEV1), forced vital capacity (FVC), maximal mid-expiratory flow rate (FEF(25-75)), and maximal expiratory flow rate (FEFmax) were obtained while breathing ambient air at baseline and 30 min after the bronchodilator treatment. Albuterol sulfate 2.5 mg was nebulized with either heliox or compressed air at 8 L/min for 8 min. When heliox was used as driving agent, additional heliox was delivered via a closed system and no entrainment of external air was allowed. Primary outcome measure was absolute change in FEV1 (deltaFEV1). There were no statistically significant differences in baseline PFTs on the two days of the study. All patients had good bronchodilator response (> or = 12% improvement in FEV1) with either driving gas. The deltaFEV1 after heliox-driven bronchodilator (HDBD) and air-driven bronchodilator (ADBD) were 0.68+/-0.38 L/sec (CI: 0.54-0.82) vs. 0.51+/-0.26 L/sec (CI: 0.42-0.60), respectively (p=0.004). The deltaFEV1 with HDBD was 49+/-90% (range -36% to 433%) more than ADBD. A subgroup analysis showed this was largely due to better response rates in patients with moderate to severe obstruction. There was more improvement in both FVC and FEFmax with HDBD than ADBD (p<0.05). The changes in FEF(25-75) were similar. We conclude that HDBD therapy improves FEV1, FVC, and FEFmax significantly more than ADBD in patients with asthma. Further large randomized studies are needed to better characterize responders and the impact on clinical outcomes.