Background The feasibility, efficacy and safety between trans-radial (TR) and trans-femoral (TF) approaches of percutaneous coronary intervention (PCI) for bifurcation lesions have not been compared. This study intended to compare outcomes between TR and TF PCI in complex coronary anatomy. Methods Among 1591 consecutive patients with bifurcation lesion treated with PCI by either TR (n=492, 31%) or TF (n=1099) approach, intra-procedural outcomes, in-hospital bleeding, and late clinical events were compared according to vascular approach methods. A total of 753 patients, 301 in TR (40%) and 452 in TF groups, were available for in-hospital bleeding. Results There were no significant differences between TR and TF approaches for procedural success in parent vessel (99.6% TR vs. 99.0% TF, p=0.24) and side branch (63.0% TR vs. 66.6% TF, p=0.16). In addition, in-hospital occurrence of Thrombosis In Myocardial Infarction major (1.1% TR vs. 0.9% TF, p>0.99) or minor bleeding (2.1% TR vs. 3.9% TF, p=0.18) were similar between groups. However, peri-procedural myocardial infarction (MI) was significantly higher in TR group (35.2% TR vs. 26.3% TF, p<0.001). During mean follow-up of 22 months, rates of cardiac death (1.2% vs. 0.5%, p=0.15), MI (0.6% vs. 1.4%, p=0.30), target lesion revascularization (4.1% vs. 5.2%, p=0.34), and major adverse cardiac events (MACE) (5.3% vs. 6.7%, p=0.27) did not statistically differ among TR and TF groups, respectively. Definite and probable stent thrombosis were also similar between TR and TF groups (0.6% vs. 0.5%, p=0.71). In a multivariate analysis, TR approach of PCI was not predictive of MACE (adjusted hazard ratio 1.15, 95% confidence interval 0.66-2.02, p=0.62). Conclusions In contrast to TF vascular approach, TR PCI is feasible and associated with similar procedural success, equivalent bleeding, and comparable late-term clinical safety and efficacy for treatment of bifurcation lesions.