Rationale: Inhaled corticosteroids (ICS) are the most effective controller medications for preventing asthma-related exacerbations based on results of clinical trials. Few studies in real-life populations have evaluated the comparative effectiveness of ICS compared to other controller medication regimens. The objective of this study was to evaluate the comparative effectiveness of the major controller medication regimens. Methods: This retrospective, cohort study of children from 2004-2010 who are part of the Population-Based Effectiveness in Asthma and Lung Diseases (PEAL) Network includes electronic data from subjects from TennCare Medicaid population and 5 large health plans, Harvard Pilgrim Health Care, Health Partners, Kaiser Permanente Northern California, Kaiser Permanente Northwest, and Kaiser Permanente Georgia. We studied children ages 4-17 years with asthma who experienced a hospitalization, ED visit, or need for oral corticosteroids in the year prior to filling a controller medication. After conducting bivariate and multivariate logistic regression using intention-to-treat analyses, we conducted time-dependent Cox regression analyses adjusting for age, gender, insurer, Charlson comorbidity score and additional co-morbid illnesses, history of ED visits, hospitalizations, oral steroid bursts in the 12 months prior to controller medication dispensing, and adherence using proportion of days covered (PDC) as a time-varying covariate based on a moving 30-day window. Our main outcome measures were asthma-related ED visits, hospitalizations, or oral corticosteroid fills in the year after filling a controller medication. Results: Of the 32,204 subjects, 53% had an incident fill of an ICS, 4% filled an ICS/long-acting beta-agonist (LABA), and 26% filled a leukotriene antagonist (LTRA). In the TennCare Medicaid population, on multivariate Cox regression, subjects treated with LTRA were less likely to experience an asthma-related ED visit (HR 0.69, CI 0.56-0.84), and just as likely to need oral corticosteroids (HR 0.86, CI 0.71-1.05) or experience a hospitalization (HR 0.74, CI 0.46-1.18). In the HMO populations, subjects treated with LTRA were just as likely to experience an asthma-related ED visit (HR 1.14, CI 0.78-1.67) or hospitalization (HR 0.18, CI 0.026-1.34), but less likely to need oral corticosteroids (HR 0.64, CI 0.44-0.94). No differences were seen between subjects dispensed ICS/LABA versus ICS. Conclusions: In these real-life populations, ICS does not appear to be superior to LTRA in preventing asthma-related exacerbations. Compared with inhaled corticosteroids, LTRA were associated with lower rates of asthma-related ED visits in pediatric asthma patients in TennCare and oral corticosteroid bursts in the HMOs, although confounding by indication may have played a role .