BACKGROUND: Adherence to evidence-based controller treatments for asthma is disappointingly low in many jurisdictions. Quantifying the burden associated with suboptimal adherence in patients with uncontrolled asthma will help establish the priorities for policymakers. OBJECTIVE: We sought to quantify the benefits in the United States of improving adherence to controller therapies in adults with uncontrolled asthma in terms of health care costs and quality-adjusted life years (QALYs). METHODS: A Markov model of asthma was created to simulate the effect of treatment with controller medications on asthma control and exacerbations over a 10-year time horizon. Health care costs and QALYs associated with the current level of adherence (status quo) were compared with a hypothetical scenario in which each patient with uncontrolled asthma at baseline will be fully adherent to an evidence-based controller therapy (the full-adherence scenario). We also evaluated the cost-effectiveness of adherence interventions as a function of their costs and improvement in the adherence. RESULTS: The status quo level of asthma management was associated with $2,786 costs and 7.55 QALYs over 10 years, whereas the corresponding values for the full-adherence scenario were $5,973 and 7.68, respectively. Consequently, the incremental cost-effectiveness ratio of the full-adherence versus the status quo was $24,515/QALY. To be cost-effective, a program that improves adherence by 50% should cost less than $130 ($450) per person annually at a willingness-to-pay value of $50,000/QALY ($100,000/QALY). Inclusion of productivity loss in the analysis resulted in the full-adherence scenario being cost-saving. CONCLUSION: Considering the extent of suboptimal adherence, our study shows that attempts in improving adherence to evidence-based therapies in patients with uncontrolled asthma can be associated with significant return on investment.