The overall safety and efficacy of transradial coronary intervention (TRI) versus coronary artery bypass grafting (CABG) for patients with unprotected left main (UPLM) disease and/or multivessel coronary disease (MVD) presenting with acute coronary syndrome (ACS) have not been established. Consecutive patients with ACS undergoing TRI with drug-eluting stent (n = 1431) or CABG (n = 651) for UPLM and/or MVD were included. A propensity-score matching was performed to adjust for differences in baseline characteristics between the 2 cohorts, yielding 524 pairs of matched patients. Median clinical follow-up was 32 months. After propensity-score adjustment, no significant difference was observed between the TRI and CABG groups in all-cause mortality (4.0% vs 5.2%; P = .375). Transradial coronary intervention was favored by a significant increase in the incidence of stroke in the CABG group (0.4% vs 1.9%; P = .020), whereas a significantly increased target vessel revascularization rate (16.8% vs 6.3%; P < .0001) observed in the TRI group favored CABG. Composite outcome (death/myocardial infarction/stroke) was comparable between the TRI and the CABG groups (8.0% vs 11.5%; P = .061). Clinical outcomes of TRI on UPLM and/or MVD for patients with ACS are comparable to CABG in composite safety outcomes with the advantage to TRI for avoiding a stroke.