This study aimed to evaluate the association between increased lipoprotein (a) [Lp(a)] and long-term outcomes in patients undergoing percutaneous coronary intervention (PCI) for in-stent restenosis (ISR).Elevated Lp(a) is demonstrated to be associated with recurrent ischemic events after PCI. However, the impact of Lp(a) in patients with ISR remains undetermined.Between January 2017 and December 2018, a total of 2086 patients who underwent PCI for ISR were consecutively enrolled. Patients were categorized as elevated group (> 30 mg/dL, n=834) and non-elevated group (≤ 30 mg/dL, n=1252) according to baseline Lp(a) levels. The primary outcome was the rate of major adverse cardiac events (MACE), defined as a composite endpoint of all-cause death, spontaneous myocardial infarction (MI), or repeat revascularization.During a median follow-up of 36 months, the primary outcome occurred in 202 of 1252 patients (26.7%) in the elevated Lp(a) group and 237 of 834 patients (21.8%) in the non-elevated Lp(a) group (adjusted hazard ratio: 1.31; 95% confidence interval: 1.08-1.58; P = 0.007), driven by higher rate of all-cause death (4.1% vs. 2.5%, P = 0.002 by Log-rank test; aHR: 1.77; 95% CI: 1.07-2.94; P = 0.03) and repeat revascularization (22.3% vs. 19.5%, P = 0.04 by Log-rank test; aHR: 1.18; 95% CI: 0.94-1.49; P = 0.16). Adding continuous or categorical Lp(a) to the Cox model led to a significant improvement in C-statistic, net reclassification, and integrated discrimination. The results were consistent across subgroups.In the current cohort of patients who underwent PCI for ISR, elevated Lp(a) at baseline is associated with higher risk of long-term MACE.