Inflammation and disorders in lipid metabolism play pivotal roles in the development and progression of in-stent restenosis (ISR). The present study aimed to investigate the association between the high-density lipoprotein (HDL)-related inflammatory indices and the risk of developing ISR among patients undergoing elective percutaneous coronary intervention (PCI). A sum of 1,471 patients undergoing elective PCI were retrospectively included and classified by tertiles of HDL-related inflammatory indices. The study endpoint was ISR. The multivariable Cox proportional hazards regression analysis with restricted cubic splines (RCS) was used to assess the associations. During a median follow-up of 62.27 months, 251 (17.06%) patients experienced ISR. The incidence of ISR increased with the increasing white blood cell-to-HDL ratio (WHR) tertiles (log-rank test, overall P=0.0082). After full adjustment, the highest tertile of WHR was significantly associated with a 1.603-fold risk of ISR (hazard ratio, 1.603; 95% confidence interval, 1.152-2.231; P=0.005) in contrast to the lowest tertile of the WHR. Results of RCS further indicated that the association between WHR and ISR was in a non-linear and dose-dependent manner (non-linear P=0.034; P overall=0.019). The lymphocyte-to-HDL ratio (LHR) and neutrophil-to-HDL ratio (NHR) were also significantly and positively associated with the risk of ISR, of which the third tertiles were at increased risk of 41.2 and 44.7% after full adjustment, respectively. Overall, lipid metabolism disorders and inflammation were interconnected in the development of ISR; therefore, HDL-related inflammatory indices, including WHR, LHR and NHR, might be potential predictors in the prognosis of elective PCI.