COPD is a leading cause of death and disability. COPD therapy goals include reducing exacerbations and improving symptom control. Single-inhaler triple therapy (SITT) or multiple-inhaler triple therapy (MITT) is indicated for patients with frequent exacerbations despite bronchodilator therapy. No available evidence compares SITT vsMITT in Spain in terms of treatment persistence, exacerbations, and other outcomes. Do COPD patients in Spain initiating SITT vsMITT have improved persistence, exacerbations, and health care resource utilization? This real-world, observational, retrospective cohort study analyzed electronic health records in the Spanish National Healthcare System BIG-PAC database to identify COPD patients aged≥ 40 years initiating SITT or MITT (using two or three inhalers) between June 1, 2018 and December 31, 2019. Comparative data on persistence (allowing up to 60days without prescription refill), exacerbation rates, and health care resource utilization and costs during 12-month follow-up were analyzed. Multivariate adjusted analyses were performed. Eligible patients (N= 4,625) initiating SITT (n= 1,011) or MITT (n= 3,614) had a mean age of 70.9 years; most were male (73.9%) with mainly moderate (62.0%) or severe (26.5%) airflow limitation. Between-cohort baseline characteristics were similar. At 12-month follow-up, SITT patients had higher persistence (hazard ratio [HR]= 1.37; 95%CI= 1.22-1.53; P< .001), reduced risk of exacerbations (HR= 0.68; 95%CI= 0.61-0.77; P= .001), and lower all-cause mortality risk (HR= 0.67; 95%CI= 0.63-0.71, P= .027), compared with MITT patients. SITT was associated with significantly reduced health care resource use (mean annual cost savings: €403 vsMITT). For both SITT and MITT, persistence was associated with improved exacerbation rates vsnonpersistence, and substantial adjusted mean annual cost savings (€2,115 and €2,700, respectively). Patients initiating SITT had a clinically relevant improvement in persistence leading to reductions in mortality, incidence of exacerbations, and health care resource use with consequent mean cost savings.