Objectives: This study assessed the feasibility of an investigational vagus nerve stimulation (VNS) device for treating acute asthma exacerbations in patients not responding to at least 1 hour of initial standard care therapy. Methods: This was a prospective, nonrandomized study of patients treated in the ED for moderate to severe acute asthma (forced expiratory volume in 1 second [FEV 1] 25% to 70% of predicted). Treatment entailed percutaneous placement of an electrode near the right carotid sheath and 60 minutes of VNS and continued standard care. VNS voltage was adjusted to perceived improvement, muscle twitching, or adverse events (AEs). All AEs, vital signs, FEV 1, perceived work of breathing (WOB), and final disposition were recorded. Results: Twenty-five subjects were enrolled. There were no serious AEs and no significant changes in vital signs. No subject required terminating VNS. One patient had minor bleeding from the procedure, and one had a hematoma and withdrew prior to VNS. AEs related to VNS were temporary and included cough (1 of 24), swallowing difficulty (2 of 24), voice change (2 of 24), and muscle twitching (14 of 24). These resolved when VNS ended. The FEV 1 improved at 15 minutes (median = 15.8%, 95% confidence interval [CI] = 9.3% to 22.4%), 30 minutes (median = 21.3%, 95% CI = 8.1% to 36.5%), and 60 minutes (median = 27.5%, 95% CI = 11.3% to 43.5%). WOB improved at 15 minutes (median = 53.9%, 95% CI = 33.7% to 73.9%), 30 minutes (median = 69.1%, 95% CI = 56.4% to 81.8%), and 60 minutes (median = 81.0%, 95% CI = 68.5% to 93.5%). Conclusions: Percutaneous VNS did not result in serious AEs and was associated with improvements in FEV 1 and perceived dyspnea. Percutaneous VNS appears to be feasible for use in the treatment of moderate to severe acute asthma in patients unresponsive to initial standard care treatment.