Asthma control requires adherence with pharmacologic therapy. A medication's mode of delivery may affect adherence. The purpose of this study was to compare medication persistence and adherence between patients newly treated with either an inhaled or injected asthma medication. Using a propensity-score-matched retrospective cohort study, we evaluated medication persistence and adherence over 1 year in adult asthma patients newly treated with omalizumab or fluticasone (500 microg)/salmeterol (50 microg) (FSC 500/50). Kaplan-Meier analysis was conducted to compare persistence between users of FSC 500/50 and omalizumab using the log-rank test. We conducted four sensitivity analyses. After propensity matching, the study sample included 213 omalizumab patients and 426 FSC 500/50 patients, with no statistically significant differences between groups on baseline measures. Mean adherence rates were 64.6% for omalizumab and 29.5% for FSC 500/50 (p < 0.0001). Fifty-four percent of omalizumab users were persistent at 1 year compared with 18.5% of FSC 500/50 users (p < 0.0001). In sensitivity analyses, we stratified patients by evidence of allergy and the results did not change. Adherence was more than twice as high and persistence was almost twice as high among omalizumab compared with FSC 500/50 users. The direction of our findings was consistent across all sensitivity analyses. In both omalizumab and FSC 500/50 cohorts, persistence decreased substantially over 1 year. Our study suggests that injected medications may have advantages in asthma treatment. A comprehensive program to improve adherence should address not just administration route but also patient factors that prevent proper medication use.