ABSTRACT: Hyperventilation has been associated with adverse effects on lung function, symptoms, and well-being in asthma. We examined whether raising end-tidal CO2 levels (ie, Pco2) compared with slow breathing is associated with improvements in asthma control, including peak flow variability.One hundred twenty patients with asthma were randomly assigned to capnometry-assisted respiratory training (CART) for raising Pco2 or slow breathing and awareness training (SLOW) for slowing respiratory rate. Patients received five weekly sessions and completed bid homework exercises over 4 weeks. Blinded assessments at baseline, posttreatment, 1- and 6-month follow-up of asthma control, Pco2, and diurnal peak flow variability were primary outcome measures. Additionally, we measured pulmonary function (spirometry, forced oscillation, exhaled nitric oxide, and methacholine challenge), symptoms, quality of life, and bronchodilator use. Because the control group received active treatment, we expected improvements in asthma control in both groups but more pronounced benefits from CART.Improvements were seen in 17 of 21 clinical indexes (81.0%) in both interventions, including the primary outcome variables asthma control (d = 0.81), peak flow variability (d = 0.54), quality of life, bronchodilator use, lung function, and airway hyperreactivity. Most improvements were sustained across the 6-month follow-up. Compared with slow breathing, CART showed greater increases in Pco2 (d = 1.45 vs 0.64 for CART vs SLOW, respectively) and greater reductions in respiratory impedance during treatment, less distress during methacholine challenge, and greater reduction in asthma symptoms at follow-up (P < .05).Brief interventions aimed at raising Pco2 or slowing respiratory rate provide significant, sustained, and clinically meaningful improvements in asthma control. Raising Pco2 was associated with greater benefits in aspects of lung function and long-term symptoms.ClinicalTrials.gov; No.: NCT00975273; URL: www.clinicaltrials.gov.