Disease management programs improve outcomes in subjects with chronic obstructive pulmonary disease (COPD), but their effect in subjects with alpha-1 antitrypsin deficiency (AATD) has not been evaluated. To assess the impact of a disease management program, applicable to subjects with AATD-associated COPD throughout the United States, on exacerbations, healthcare resource utilization and health-related quality of life (HRQoL). The Alpha-1 Disease Management and Prevention Program (ADMAPP) consisted of comprehensive written educational patient-directed material for self-study and treatment plans. Program reinforcement was performed through monthly phone calls by specialized coordinators. Outcomes were collected prospectively for 12 months before, and 12 months after enrollment into the program. Exacerbations and healthcare resource utilization were recorded monthly. HRQoL was measured with the St George's Respiratory Questionnaire (SGRQ) every 6 months and the Short Form-36 (SF-36) every 12 months. A total of 878 subjects completed the 2-year study. During the intervention year, there was a significant increase in the use of long-acting bronchodilators, better compliance with oxygen therapy, and more use of steroid courses during exacerbations. Total exacerbation rates, unscheduled physician visits and emergency room visits significantly decreased. There was also a statistically significant slowing in the deterioration of the SGRQ's activity domain, while total SGRQ scores remained stable during the study. Significant improvements were observed in some of the SF-36 domains, particularly in the general health domain. The ADMAPP improved health outcomes in subjects with AATD-associated COPD.