Chlorthalidone (CLTD) and hydrochlorothiazide (HCTZ) are widely used thiazide diuretics for hypertension management. This study aimed to evaluate and compare the cardiovascular outcomes of patients treated with CLTD versus HCTZ. This multicenter, retrospective cohort study utilized data from the Korea University Medical Center, derived from electronic health records. A total of 14 257 hypertensive patients treated with either CLTD (n = 1920) or HCTZ (n = 12 337) were identified. Patients were matched 1:1 using propensity scores, resulting in 1606 patients in each treatment group. Demographic and clinical characteristics, incidence of major adverse cardiovascular events (MACE), and safety profiles were analyzed. Baseline characteristics after propensity score matching were well balanced between the two groups. The average age was 61.8 ± 14.6 years for CLTD users, with 59.3% being male. The 3-year MACE occurred in 1.2% of the CLTD group compared with 1.4% of the HCTZ group (hazard ratio 0.91, p = 0.77). For secondary outcomes, cardiovascular mortality was 0.2% in both groups (p = 0.92). Myocardial infarction occurred in 0.3% of CLTD users and 0.4% of HCTZ users (p = 0.65). The incidence of hypokalemia was 19.2% in the CLTD group versus 16.7% in the HCTZ group (p = 0.07). In conclusion, in hypertensive patients, CLTD and HCTZ showed comparable cardiovascular outcomes and safety profiles.