Compared with placebo, olmesartan has been linked to numerical imbalances in cardiovascular mortality. There is a paucity of contemporary real-world evidence on this agent for different study populations. This study investigated the clinical outcomes of olmesartan and other antihypertensives in patients with advanced hypertension. This multicenter retrospective study used data from the Korea University Medical Center database, built from electronic health records. Patients prescribed at least two antihypertensive medications as a combined therapy were followed-up for 3 years. The primary outcome was a composite of all-cause mortality, myocardial infarction (MI), stroke, and hospitalization for heart failure. Adjusted outcomes were compared using propensity score (PS) matching. Among 24 806 patients, 4050 (16.3%) were olmesartan users between January 2017 and December 2018. The average patient age was 64 years, 45% were women, and 41% had diabetes. Olmesartan users were younger and less likely to have diabetes mellitus or chronic kidney disease. In PS-matched cohort, the 3-year cumulative incidences of the primary outcome were similar between the two groups (P = 0.91). The cumulative incidence of MI at 3 years was 1.4% in olmesartan users (4.8 per 1000 person-years) and 1.5% in active comparators (5.2 per 1000 person-years; P = 0.74). Olmesartan also showed similar safety profiles, including acute kidney injury and newly started dialysis. In real-world practice, olmesartan use in combination therapy resulted in similar cardiovascular outcomes when compared with those of active comparators, and our findings did not show any conclusive evidence that olmesartan is harmful in patients with hypertension.