Autogenic drainage (AD) is used for airway clearance in individuals with cystic fibrosis (CF). The mechanical insufflator-exsufflator (MI-E) device is commonly used in patients with neuromuscular diseases for airway clearance by increasing inspiratory volume and expiratory flow. MI-E use has not been studied extensively in CF patients. To examine whether there are advantages to using the MI-E device in patients with CF. Fourteen males and eight females from the national center for CF, with an average FEV1 of 54% were recruited DESIGN: Prospective cross-over trial (IRB 3009-16-SMC). Subjects received either AD or MI-E in a random order. Sputum was collected and weighed immediately after treatment. Subjects performed lung function tests at baseline, 20 minutes after and 1 hour after treatment; additionally, a 2-minute walk test was performed at the end of all lung function tests. Saturation, dyspnea scores while resting and after a 2-minute walk and subjective fatigue were recorded. Thirty-six percent more sputum was collected following MI-E than AD treatment (P < .0001). A significant difference in saturation in response to the 2MWT was noted in both treatments significantly less desaturation was recorded after the 2MWT in the MI-E treatment (P < .01). Treatment with the MI-E was more effective for clearing sputum in CF subjects, initial evidence suggests that the MI-E may be successfully incorporated into treatment protocols. Further studies are needed to assess the long-term benefits of MI-E in patients with CF.