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Objective: To investigate the factors associated with recurrent in-stent restenosis (ISR) after drug-eluting stent (DES) implantation and to establish a screening model. Methods: This cross-sectional study enrolled patients who underwent DES implantation and subsequent coronary angiography at the Second Hospital of Dalian Medical University from January 2020 to July 2023, with confirmed ISR. Patients were divided into an ISR group (first episode) and a recurrent ISR (R-ISR) group (≥2 episodes at the same lesion). Clinical data, laboratory parameters, echocardiographic findings, and coronary angiography results were collected. Correlation analysis and multivariate logistic regression were performed to identify independent factors associated with R-ISR. A logistic regression model was constructed using stepwise regression, and its screening value was assessed by the area under the receiver operating characteristic curve (AUC). Results: A total of 292 patients with DES restenosis were included, aged (66.5±9.5) years, with 73.6% male. There were 202 in the ISR group and 90 in the R-ISR group. Correlation analysis showed that R-ISR was associated with lactate dehydrogenase (LDH) (r_pb=-0.159, P=0.007), number of stents (r_pb=0.256, P0.001), neutrophil-to-lymphocyte ratio (NLR) (r_pb=0.350, P0.001), and interleukin-1β (r_pb=0.324, P0.001). Multivariate logistic regression identified number of stents (OR=1.271, 95%CI 1.094-1.477, P=0.002), LDH (OR=0.989, 95%CI 0.982-0.996, P=0.002), NLR (OR=1.370, 95%CI 1.131-1.660, P=0.001), and interleukin-1β (OR=1.190, 95%CI 1.019-1.388, P=0.028) as independent factors for R-ISR. The combined model of these four indicators yielded an AUC of 0.742 (95%CI 0.641-0.843). Conclusions: LDH, number of stents, NLR, and IL-1β are independent related factors for R-ISR. The model based on these four variables demonstrates good predictive value for screening R-ISR, providing a reference for early identification and intervention in high-risk patients.