Background: Although 1-stent with provisional approach is the preferred strategy for the treatment of bifurcation lesions, the optimal treatment strategy according to lesion location is still debatable. This study aimed to identify whether clinical outcomes according to treatment strategy differed between left main (LM) and non-LM bifurcation lesions in the second-generation drug-eluting stent era. Methods: The Coronary Bifurcation Stenting registry III is a retrospective multicenter registry of 2648 patients with bifurcation lesions who underwent percutaneous coronary intervention with second-generation drug-eluting stent. Among the study population, 935 (35.3%) patients had an LM bifurcation lesion. The primary outcome was target lesion failure, a composite of cardiac death, myocardial infarction, and target lesion revascularization. Results: Median follow-up duration was 53 months. LM bifurcation was associated with a higher risk of target lesion failure (HR _adj , 1.846 [95% CI, 1.317–2.588]; P <0.001) than non-LM bifurcation. Two-stent strategy was more frequently applied in patients with LM bifurcation than in patients with non-LM bifurcation (27.1% versus 11.7%; P <0.001). In the LM bifurcation group, compared with the 1-stent strategy, the 2-stent strategy showed a significantly higher risk of target lesion failure (2-stent versus 1-stent, 17.4% versus 10.6%; HR _adj , 1.848 [95% CI, 1.045–3.266]; P =0.035), mainly driven by the higher rate of target lesion revascularization (15.3% versus 5.5%; HR _adj , 2.698 [95% CI, 1.276–5.706]; P =0.009). However, the risk of cardiac death or myocardial infarction did not differ between the 2 groups (4.4% versus 6.6%; HR _adj , 0.694 [95% CI, 0.306–1.572]; P =0.381). For patients with non-LM-bifurcation, there was no significant difference in the rate of target lesion failure between 1-stent and 2-stent strategies (5.6% versus 6.3%; HR _adj , 0.925 [95% CI, 0.428–2.001]; P =0.843). Conclusions: Even in the second-generation drug-eluting stent era, the 1-stent strategy, if possible, should initially be considered the preferred approach for the treatment of LM bifurcation lesions. Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT03068494.