ACE (angiotensin-converting enzyme) inhibitors and angiotensin receptor blockers (ARBs) are equally guideline-recommended first-line treatments for hypertension, yet few head-to-head studies exist. We compared the real-world effectiveness and safety of ACE inhibitors versus ARBs in the first-line treatment of hypertension. We implemented a retrospective, new-user comparative cohort design to estimate hazard ratios using techniques to minimize residual confounding and bias, specifically large-scale propensity score adjustment, empirical calibration, and full transparency. We included all patients with hypertension initiating monotherapy with an ACE inhibitor or ARB between 1996 and 2018 across 8 databases from the United States, Germany, and South Korea. The primary outcomes were acute myocardial infarction, heart failure, stroke, and composite cardiovascular events. We also studied 51 secondary and safety outcomes including angioedema, cough, syncope, and electrolyte abnormalities. Across 8 databases, we identified 2 297 881 patients initiating treatment with ACE inhibitors and 673 938 patients with ARBs. We found no statistically significant difference in the primary outcomes of acute myocardial infarction (hazard ratio, 1.11 for ACE versus ARB [95% CI, 0.95–1.32]), heart failure (hazard ratio, 1.03 [0.87–1.24]), stroke (hazard ratio, 1.07 [0.91–1.27]), or composite cardiovascular events (hazard ratio, 1.06 [0.90–1.25]). Across secondary and safety outcomes, patients on ARBs had significantly lower risk of angioedema, cough, pancreatitis, and GI bleeding. In our large-scale, observational network study, ARBs do not differ statistically significantly in effectiveness at the class level compared with ACE inhibitors as first-line treatment for hypertension but present a better safety profile. These findings support preferentially prescribing ARBs over ACE inhibitors when initiating treatment for hypertension.