The purpose of this study was to evaluate the efficacy of heliox-driven continuous nebulizers in the management of moderate to severe asthma exacerbations in the Emergency Department (ED). The trial was a prospective, randomized, double-blind, controlled trial in a university Emergency Department (volume 65,000 patients/year) of patients 18–55 years of age with acute asthma exacerbations. Patients were placed on continuous nebulizers driven by 70:30 heliox or air with 30% O2. Respiratory rate, peak expiratory flow rate (PEFR), forced expiratory volume at 1 s (FEV1), and Borg dyspnea scale were measured at 0 and 2 h. Disposition and patient satisfaction were also assessed. A total of 36 patients completed the study (18 heliox, 18 air). There was no difference between groups in baseline variables. There was significant interval improvement within both groups at 2 h in PEFR, FEV1, Borg, and respiratory rate. There was no significant difference between heliox 70:30 and air/oxygen in PEFR [mean between-group improvement difference 17 liters/min, 95% confidence interval (CI) −20–51], FEV1 (0.03 liters/sec, 95% CI −0.22–0.30), or respiratory rate (mean between-group improvement difference 0.5, 95% CI −2.7–3.8). There was a significant improvement in the patients’ perceived dyspnea as measured by the Borg dyspnea scale at 2 h in the heliox group (1.6, 95% CI 0.3–3.0). In this trial of patients with moderate-severe asthma exacerbation, heliox-driven continuous nebulizers failed to demonstrate an improvement in respiratory rate, oxygen saturation, PEFR, or FEV1 at 2 h. However, there was a significant improvement in the patients’ perceived dyspnea on heliox over air/oxygen measured by the Borg dyspnea scale.