Background: There is a paucity of data regarding the long-term clinical outcomes of first- versus second-generation drug-eluting stent (DES), especially when used to treat complex lesions such as bifurcation lesions. Objectives: The current study compares the efficacy and safety of first- versus second-generation DES at the 5-year follow-up in patients who underwent bifurcation percutaneous coronary intervention (PCI). Methods: A total of 5,498 patients with a bifurcation lesion who underwent PCI were pooled at a single patient level from COBIS (Coronary Bifurcation Stenting) registries II and III. Five-year target lesion failure (TLF) (the composite of cardiac death, myocardial infarction [MI], and target lesion revascularization [TLR]) and cardiac death or MI were compared between the use of first-generation DES (n = 2,436) and second-generation DES (n = 3,062) during PCI. Propensity score matching was performed to reduce selection bias. Results: After a 1:1 propensity score matching procedure was conducted, the cohort consisted of 1,702 matched pairs. Patients treated with second-generation DES had a significantly lower risk of TLF at 5 years than those treated with first-generation DES in both overall and propensity-matched populations (matched hazard ratio [HRmatched]: 0.576; 95% confidence interval [CI]: 0.456 to 0.727; p <0.001). There were no significant differences in risk of a composite of cardiac death or MI between the 2 groups (HRmatched: 0.782; 95% CI: 0.539 to 1.133, P = 0.193). However, among patients who required a 2-stent technique, use of the second-generation DES reduced cardiac death or MI (HRmatched:0.422; 95% CI: 0.209 to 0.851, P = 0.016). On the other hand, among patients who required a one-stent technique, the risk of a composite of cardiac death or MI was similar between the 2 groups (HRmatched: 1.046; 95% CI: 0.664 to 1.650, P = 0.845). There was a significant interaction between stent generation and treatment strategy for cardiac death or MI (interaction P = 0.029). Conclusions: In patients treated with PCI for a bifurcation lesion, the use of second-generation DES was associated with a significantly reduced risk of 5-year TLF than the use of first-generation DES. (Korean Coronary Bifurcation Stenting Registry II [NCT01642992]; COBIS II) (Korean Coronary Bifurcation Stenting Registry III [NCT03068494] COBIS III)