The clinical benefit of β-blockers in modern reperfusion era is not well determined. We investigated the impact of β-blockers in acute coronary syndrome (ACS) after percutaneous coronary intervention. From the Grand-DES registry, a patient-level pooled registry consisting of 5 Korean multicenter prospective drug-eluting stent registries, a total of 6,690 ACS patients were included. Prescription records of dose and type of β-blockers were investigated trimonthly from discharge. Patients were categorized by the mean value of doses during the follow-up (≥50% [high-dose], ≥25% to <50% [medium-dose], and <25% [low-dose] of the full dose that was used in each randomized clinical trial) and vasodilating property of β-blockers. Three-year cumulative risk of all-cause death, cardiac death, and myocardial infarction were assessed. Patients receiving β-blockers were associated with a lower risk of all-cause and cardiac death compared with those not receiving β-blockers (adjusted hazard ratio [aHR] 0.29, 95% confidence interval [CI] 0.24 to 0.35 for all-cause death; aHR 0.27, 95% CI 0.21 to 0.34 for cardiac death). Medium-dose β-blocker group was associated with a lower risk of cardiac death compared with high- and low-dose β-blocker groups (aHR 0.49, 95% CI 0.25 to 0.96, for high-dose; aHR 0.46, 95% CI 0.29 to 0.74, for low-dose). Patients receiving vasodilating β-blockers were associated with a lower risk of cardiac death compared with those receiving conventional β-blockers (aHR 0.58, 95% CI 0.40 to 0.84). In conclusion, β-blocker therapy was associated with better clinical outcomes in patients with ACS, especially with medium-dose and vasodilating β-blockers.