Abstract Background Recent trials have shown intravascular imaging (IVI)-guided percutaneous coronary intervention (PCI) has prognostic benefit compared with angiograph-guided PCI in complex coronary artery lesions. However, it is unclear whether this benefit is affected by overall complexity of target lesions in each patient. Objectives To investigate an impact of the number of complex lesion features on the benefit of IVI-guided PCI. Methods A total of 4,611 patients with complex coronary artery lesions from the RENOVATE-COMPLEX-PCI trial (n=1,639) and the institutional registry of a medical center (n=2,972) were classified according to the number of complex lesion features found in each patient. The primary outcome was a target vessel failure (TVF) at 3 years, a composite of cardiac death, target vessel myocardial infarction, or target vessel revascularization. Results The best cut-off number of complex lesion features for the risk of TVF was 3 and patients with ≥3 complex lesion features had higher risk of TVF than those with <3 complex lesion features (11.0% vs. 7.2%; HR 1.59, 95% CI 1.28-1.96, P<0.001). IVI-guided PCI significantly reduced the risk of TVF compared to angiography-guided PCI in both groups (≥3 complex lesion features: 7.4% vs. 14.4%, HR 0.49; 95% CI 0.35-0.69, P<0.001; <3 complex lesion features: 5.7% vs. 8.1%; HR 0.72, 95% CI 0.53-0.98, P=0.039). The benefit of IVI-guided PCI tended to increase as the number of complex lesion features increased (absolute risk reduction for TVF: -0.012 vs. -0.027 vs. -0.055 vs. -0.077, respectively, for the number of complex lesion features 1 vs. 2 vs. 3 vs. ≥4, interaction P=0.048). Conclusion In patients with complex coronary artery lesions, IVI-guided PCI reduced the risk of TVF regardless of overall complexity of the target lesions in each patient. The prognostic benefit of IVI-guided PCI tended to increase as patients had more complex lesion features.Clinical Outcomes