BACKGROUND: We previously reported the use of minimal stent area to predict angiographic in-stent restenosis after drug-eluting stent implantation for unprotected left main (LM) disease. We aimed to evaluate the optimal minimal stent area criteria for up-front LM 2-stenting based on long-term clinical outcomes. METHODS: We identified 292 consecutive patients with LM bifurcation stenosis who were treated using the crush technique. The final minimal stent area was measured in the ostial left anterior descending artery (LAD), ostial left circumflex artery (LCX), and distal LM. The primary outcome was 5-year major adverse cardiac events, including all-cause death, myocardial infarction, and target lesion revascularization. RESULTS: The minimal stent area cutoff values that best predicted the 5-year major adverse cardiac events were 11.8 mm2 for distal LM (area under the curve, 0.57; P=0.15), 8.3 mm2 for LAD ostium (area under the curve, 0.62; P=0.02), and 5.7 mm2 for LCX ostium (area under