Objective: To detect the expression levels of long non-coding RNA (lncRNA) X-inactive specific transcript (XIST) and silent information regulator 2 homolog 1 (SIRT1) in serum of patients with type 2 diabetes mellitus (T2DM), and to explore the correlation between it and diabetes retinopathy (DR) and its diagnostic value. Methods: A total of 214 T2DM patients admitted to our hospital from January 2022 to February 2023 were selected for this study. Serum lncRNA XIST and SIRT1 levels were detected. Results: Serum lncRNA XIST and SIRT1 levels in control group, non-DR group and DR Group were decreased successively (P < 0.05). There was a significant positive correlation between serum lncRNA XIST and SIRT1 levels in DR Patients (r=0.639, P < 0.05). ROC analysis showed that the AUC of serum lncRNA XIST and SIRT1 combined predicted DR Was 0.940, which was higher than that of serum lncRNA XIST and SIRT1 alone (0.855, 0.875). Logistic regression analysis showed that lncRNA XIST (OR=0.752) and SIRT1 (OR=0.694) were the influencing factors for the occurrence of DR (P<0.05).Conclusion: Serum lncRNA XIST and SIRT1 levels were decreased in patients with DR, and lncRNA XIST combined with SIRT1 had better efficacy in evaluating the occurrence of DR.