Objective: In-stent restenosis (ISR) is an unfavorable complication that occurs in patients after coronary stenting. Despite the progress with advent of modern DES and new antiplatelet agents, restenosis still hampers PCI short- and long-term results. The aim of this study was to investigate whether circulating miRNA-223, which is associated with HDL particles and involved in cholesterol efflux pathway, have diagnostic capability for determining ISR. ----- Methods: This case-control study comprised 21 ISR and 26 NISR patients. The level of miRNA-223 expression was evaluated by TaqMan Real-Time PCR, quantified by the comparative method (fold change) and normalized to U6 expression. ----- Results: Patients in ISR and NISR groups were not different in terms of demographic, clinical, and biochemical parameters, except that the percentage of patients who had DES was significantly greater in the NISR group (88.9%) in comparison with the ISR group (50%). The serum expression of miRNA-223 in ISR patients was 3.277 ± 0.9 times greater than that in NISR group (p = 0.016). In addition, the results of binary logistic regression demonstrated that the high level of serum miRNA-223 was strongly and positively associated with the ISR risk (OR: 17.818, 95% CI: 1.115-284.623, p = 0.042) after adjustment for age, sex, HDL-C, LDL-C, FBS, and statin consumption. ----- Conclusion: Elevated serum level of miRNA-223 might be helpful in predicting the occurrence of ISR. Further confirmation in future large-scale studies is warranted.