Aim To investigate the predictive value of lipoprotein(a) [Lp(a)] combined with systemic inflammatory response index (SIRI) on in-stent restenosis (ISR) after percutaneous coronary intervention (PCI) in patients with coronary heart disease. Methods The clinical data of 770 patients with coronary heart disease who underwent PCI in the Department of Cardiovascular Medicine of the First Affiliated Hospital of Xinjiang Medical University from May 2012 to December 2024 and underwent coronary angiography six months after surgery were collected. According to the imaging results, the patients were divided into ISR group (n＝194) and non-ISR group (n＝576). Multivariate Logistic regression and random forest model were used to analyze the independent risk factors of ISR. Risk factors included in the analysis were glycated hemoglobin, SIRI, Lp(a), lymphocyte count, apolipoprotein A1 (ApoA1) and residual cholesterol. Results The levels of Lp(a) and SIRI in the ISR group were significantly higher than those in the non-ISR group (P＜0.05). ROC curve analysis showed that the area under the curve of the combined indicator of Lp(a) and SIRI was 0.789, which was higher than the 0.652 of the single indicator Lp(a) and 0.778 of SIRI. Conclusion Lp(a) and SIRI are independent risk factors for the occurrence of ISR after PCI, and the combination of Lp(a) and SIRI can better predict the occurrence of ISR.