BACKGROUND: Based on results of clinical trials, inhaled corticosteroids (ICS) are the most-effective controller medications for preventing asthma-related exacerbations, yet few studies in real-life populations have evaluated the comparative effectiveness of ICS. OBJECTIVE: To determine the likelihood of asthma exacerbations among children with asthma after initiation of controller medications: ICS, leukotriene antagonists (LTRA), and ICS-long-acting beta-agonist (LABA) combination therapy. METHODS: This was a retrospective cohort study of subjects who were part of the Population-Based Effectiveness in Asthma and Lung Diseases Network. We conducted Cox regression analyses by adjusting for baseline covariates, adherence by using proportion of days covered, and high-dimensional propensity scores. The main outcome measurements were emergency department visits, hospitalizations, or oral corticosteroid use. RESULTS: Our population included 15,567 health plan subjects and 10,624 TennCare Medicaid subjects with uncontrolled asthma. Overall adherence to controller medications was low, with no more than 50% of the subjects refilling the medication after the initial fill. For subjects with allergic rhinitis, the subjects in TennCare Medicaid treated with LTRAs were less likely to experience ED visits (hazard ratio 0.44 [95% CI, 0.21-0.93]) compared with the subjects treated with ICS. For all other groups, the subjects treated with LTRA or ICS-LABA were just as likely to experience ED visits or hospitalizations, or need oral corticosteroids as the subjects treated with ICS. CONCLUSION: Risks of asthma-related exacerbations did not differ between children who initiated LTRA and ICS. These findings may be explainable by LTRA, which has similar effectiveness as ICS in real-life usage by residual confounding by indication or other unmeasured factors.