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In-stent restenosis (ISR) remains a major obstacle in percutaneous coronary intervention (PCI) in patients with coronary heart disease. Although previous studies suggest that remnant cholesterol (RC) may play a significant role in ISR, the exact relationship remains underexplored. This study aims to investigate the predictive value of RC levels for the risk of ISR following PCI and drug-eluting stent (DES) implantation. A retrospective study was conducted on 548 CHD patients who underwent PCI at the First Affiliated Hospital, Sun Yat-sen University, between January 2018 and December 2023. The primary outcome was the presence of ISR, defined as ≥50% in-segment diameter stenosis. Patients were divided into 2 groups: ISR (n = 56) and non-ISR (n = 492). The ISR group exhibited significantly higher RC levels compared to the non-ISR group (P = .004). Multivariable logistic regression analyses revealed that RC (odds ratio [OR] = 2.873, 95% CI: 1.121-7.364, P = .028), diabetes (OR = 2.656, 95% CI: 1.474-4.786, P = .001), and alcohol consumption (OR = 2.988, 95%CI: 1.082-8.251, P = .035) were independent predictors of ISR. The predictive logistic model combining RC with 6 clinically relevant factors (age, gender, smoking status, alcohol consumption, hypertension, and diabetes) for ISR showed a higher area under the curve of 0.721 (95% CI: 0.654-0.789), compared to the model with only RC, which had an area under the curve of 0.618 (95% CI: 0.547-0.690). Increased RC levels were significantly associated with ISR in CHD patients following PCI. This study suggests that RC could be a potential risk factor and predictive marker for the development of ISR after DES implantation.