We compared the impact of 3 confounding adjustment procedures-covariate-adjusted regression, propensity score regression, and high-dimensional propensity score regression-to assess the effects of selected asthma controller medication use (leukotriene antagonists and inhaled corticosteroids) on the following 4 asthma-related adverse outcomes: emergency department visits, hospitalizations, oral corticosteroid use, and the composite outcome of these. We examined a cohort of 24,680 new users who were 4-17 years of age at the incident dispensing from the Population-Based Effectiveness in Asthma and Lung Diseases (PEAL) Network of 5 commercial health plans and TennCare, the Tennessee Medicaid program, during the period January 1, 2004, to December 31, 2010. The 3 methods yielded similar results, indicating that pediatric patients treated with leukotriene antagonists were no more likely than those treated with inhaled corticosteroids to experience adverse outcomes. Children in the TennCare population who had a diagnosis of allergic rhinitis and who then initiated the use of leukotriene antagonists were less likely to experience an asthma-related emergency department visit. A plausible explanation is that our data set is large enough that the 2 advanced propensity score-based analyses do not have advantages over the traditional covariate-adjusted regression approach. We provide important observations on how to correctly apply the methods in observational data analysis and suggest statistical research areas that need more work to guide implementation.