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 mm ² for distal LM (area under the curve, 0.57; P =0.15), 8.3 mm ² for LAD ostium (area under the curve, 0.62; P =0.02), and 5.7 mm ² for LCX ostium (area under the curve, 0.64; P =0.01). Using these criteria, the risk of 5-year major adverse cardiac events was significantly associated with stent underexpansion in the LAD ostium (hazard ratio, 3.14; [95% CI, 1.23–8.06]; P =0.02) and LCX ostium (hazard ratio, 2.60 [95% CI, 1.11–6.07]; P =0.03) but not in the distal LM (hazard ratio, 0.81 [95% CI, 0.34–1.91]; P =0.63). Patients with stent underexpansion in both ostial LAD and LCX had a significantly higher rate of 5-year major adverse cardiac events than those with no or 1 underexpanded stent of either ostium ( P <0.01). CONCLUSIONS: Stent underexpansion in the LAD and LCX ostium was significantly associated with long-term outcomes in patients who underwent up-front 2-stenting for LM bifurcation stenosis.