BACKGROUND Angiotensin II receptor blockers (ARBs) and angiotensin‐converting enzyme inhibitors (ACEIs) block distinct components of the renin‐angiotensin system. Whether this translates into differential effects on cardiovascular disease events remains unclear. METHODS AND RESULTS We used the ACCORD‐BP (Action to Control Cardiovascular Risk in Diabetes–Blood Pressure) trial and the SPRINT (Systolic Blood Pressure Intervention Trial) to emulate target trials of new users of ARBs versus ACEIs on cardiovascular disease events (primary outcome) and death (secondary outcome). We estimated marginal cause‐specific hazard ratios (HRs) and treatment‐specific cumulative incidence functions with inverse probability of treatment weights. We identified 3298 new users of ARBs or ACEIs (ACCORD‐BP: 374 ARB versus 884 ACEI; SPRINT: 727 ARB versus 1313 ACEI). For participants initiating ARBs versus ACEIs, the inverse probability of treatment weight rate of the primary outcome was 3.2 versus 3.5 per 100 person‐years in ACCORD‐BP (HR, 0.91 [95% CI, 0.63–1.31]) and 1.8 versus 2.2 per 100 person‐years in SPRINT (HR, 0.81 [95% CI, 0.56–1.18]). There were no appreciable differences in pooled analyses, except that ARBs versus ACEIs were associated with a lower death rate (HR, 0.56 [95% CI, 0.37–0.85]). ARBs were associated with a lower rate of the primary outcome among subgroups of male versus female participants, non‐Hispanic Black versus non‐Hispanic White participants, and those randomly assigned to standard versus intensive blood pressure ( P _interaction : <0.01, 0.05, and <0.01, respectively). CONCLUSIONS In this secondary analysis of ACCORD‐BP and SPRINT, new users of ARB‐ versus ACEI‐based antihypertensive medication regimens experienced similar cardiovascular disease events rates, with important subgroup differences and lower rates of death overall. REGISTRATION URL: https://www.clinicaltrials.gov ; Unique identifiers: NCT01206062, NCT00000620.