Rationale: Individuals with cystic fibrosis (CF) experience frequent acute pulmonary exacerbations, which lead to decreased lung function and reduced quality of life. Objectives: The goal of this study was to determine if an intervention directed toward early detection of pulmonary exacerbations using home spirometry and symptom monitoring would result in slower decline in lung function than in control subjects. Methods: We conducted a multicenter, randomized trial at 14 CF centers with subjects at least 14 years old. The early intervention arm subjects measured home spirometry and symptoms electronically twice per week. Sites were notified if a participant met criteria for an exacerbationandcontactedparticipantstodetermineiftreatmentfor acute exacerbation was required. Participants in the usual care arm were seen every 3 months and were asked to contact the site if they were concerned about worsening pulmonary symptoms. Measurements and Main Results: The primary outcome was the 52-week change in FEV1. Secondary outcomes included time to first exacerbationandsubsequentexacerbation,qualityoflife,andchangein weight. A total of 267 patients were randomized, and the study arms were well matched at baseline. There was no significant difference betweenstudyarmsin52-weekmeanchangeinFEV1slope(meanslope difference, 0.00 L, 95% confidence interval, 20.07 to 0.07; P = 0.99). The early intervention arm subjects detected exacerbations more frequently than usual care arm subjects (time to first exacerbation hazard ratio, 1.45; 95% confidence interval, 1.09 to 1.93; P = 0.01). Adverseeventswerenotsignificantlydifferentbetweentreatmentarms. Conclusions: An intervention of home monitoring among patients with CF was able to detect more exacerbations than usual care, but this did not result in slower decline in lung function. Clinical trial registered with www.clinicaltrials.gov (NCT01104402).