Background Medication non-adherence can result in considerable morbidity, mortality, and costs. The Pharmacy Quality Alliance hypertension medication adherence measure is used by US healthcare payers and providers to assess renin-angiotensin system antagonist medication adherence. However, associations between renin-angiotensin system antagonist adherence as calculated in quality measures, and healthcare service use and expenditure in commercial populations over a 1-year timeframe has not been assessed. Methods and Results This retrospective cohort study used eligible commercially insured individuals from the Truven Health MarketScan Commercial Claims and Encounters Research Databases (2009-2015). Generalized linear models with log link and gamma distribution (expenditure) or negative binomial distribution (usage) assessed relationships between hypertension adherence (≥80% proportion of days covered) and healthcare use and expenditures (in 2015 US dollars) while adjusting for covariates (age, sex, geographic region; health plan; Deyo-Charlson Comorbidity Index, number of chronic medications, and treatment naivety). Beta coefficients were used to compute cost ratios and rate ratios. A total of 4 842 058 subjects were eligible; of those, 3 310 360 (68%) were adherent (adherent mean age 53.3±8.0 years, 55.9% men; non-adherent mean age 50.3±9.1 years, 53.1% men). Adherence was associated with fewer inpatient (rate ratios, 0.612; 95% CI, 0.607-0.617) and outpatient visits (rate ratios, 0.995; 95% CI, 0.994-0.997); and lower total costs (cost ratios, 0.876; 95% CI, 0.874-0.878) compared with non-adherence. Adherence was associated with lower average per member per month total costs ($97.98) compared with non-adherence. Conclusions Adherence to renin-angiotensin system antagonists was associated with fewer outpatient and inpatient visits, and lower total costs compared with non-adherence in a 1-year time frame.