This study evaluated the prognostic value of remnant lipoprotein cholesterol (RLP-C) as a predictor of in-stent restenosis (ISR) after drug-eluting stent (DES) implantation in patients with coronary artery disease (CAD). Consecutive patients with CAD (n = 612) who underwent both successful coronary DES implantation and follow-up angiography ranging from 6 to 24 months were enrolled. The independent predictors of ISR were explored by multivariate logistic regression analysis; 95 (15.52%) patients were identified to have ISR. Multivariate logistic regression analysis showed that RLP-C concentration (odds ratio [OR]: 4.245, 95% confidence interval [CI]: 2.493-7.229), age (OR: 1.026, 95% CI: 1.002-1.051), diabetes mellitus (DM; OR: 1.811, 95% CI: 1.134-2.892), and lesion length (OR: 1.013, 95% CI: 1.002-1.024) were associated with ISR. Via subgroup analysis, we found that RLP-C was independently associated with ISR in both CAD with DM (OR: 4.154, 95% CI: 1.895-9.104) and CAD without DM (OR: 4.455, 95% CI: 2.097-9.464) groups. In the analysis of the receiver operating characteristics curve, RLP-C level >0.515 mmol/L exhibited 77.9% sensitivity and 56.5% specificity (area under the curve: 0.705, 95% CI: 0.648-0.762) in predicting ISR. In conclusion, RLP-C is independently associated with the development of ISR in patients with CAD after DES implantation.