Objective To observe the clinical factors and macular microstructural changes associated with the development of epiretinal membrane (ERM) in patients with diabetic macular edema (DME) after intravitreal injection of anti-vascular endothelial growth factor (VEGF) drugs. MethodsA retrospective case-control study. A total of 85 patients (108 eyes) with DME, who were diagnosed and treated with intravitreal anti-VEGF injections at Tianjin Eye Hospital between October 2019 and September 2022, were included in this study. Detailed clinical data were collected, including age, duration of diabetes, best-corrected visual acuity (BCVA), and the cumulative number of intravitreal anti-VEGF injections. BCVA examination was performed using the international standard visual acuity chart, which was converted into logarithm of the minimum angle of resolution (logMAR) for statistical analysis. Optical coherence tomography (OCT) was used to measure central macular thickness (CMT), quantify hyperreflective foci (HRF), and assess the presence of disorganization of the retinal inner layers (DRIL). Eyes were divided into an ERM group and a non-ERM group based on the presence of ERM, comprising 37 eyes (34.3%, 37/108) and 71 eyes (65.7%, 71/108), respectively. Clinical characteristics and OCT parameters were compared between the two groups. Multivariate logistic regression analysis was performed to identify independent factors associated with ERM formation, and a five-fold cross-validation approach was used to evaluate the predictive performance of the regression model. ResultsThe mean age in the ERM group and non-ERM group was (58.73±10.76) and (53.51±12.44) years, respectively. The duration of diabetes was (17.89±8.60) and (10.62±6.63) years, respectively. The logMAR BCVA was 0.79±0.36 and 0.62±0.39, respectively. The cumulative number of intravitreal anti-VEGF injections was 6.43±3.81 and 3.79±3.58, respectively. The CMT was (294.95±24.93) μm in the ERM group and (274.66±29.88) μm in the non-ERM group, while the HRF count was 10.43±4.35 and 7.46±4.17, respectively. The presence of DRIL was observed in 11 eyes (29.7%, 11/37) in the ERM group and 6 eyes (8.5%, 6/71) in the non-ERM group. Compared with the non-ERM group, patients in the ERM group were older, had a longer duration of diabetes, worse visual acuity, and received a higher number of intravitreal anti-VEGF injections. These differences were statistically significant (t=?2.267, ?4.495, ?2.263, ?3.491; P＜0.05). In addition, the ERM group showed significantly increased CMT (t=?3.743), higher HRF counts (t=?3.413), and a higher proportion of DRIL (χ2=8.304), all with statistical significance (P＜0.05). Multivariate logistic regression analysis identified diabetes duration [odds ratio (OR)=1.113, 95% confidence interval (CI) 1.002-1.238, P=0.049], CMT (OR=1.027, 95%CI 1.005-1.049, P=0.014), HRF count (OR=1.187, 95%CI 1.053-1.337, P=0.005), and the cumulative number of intravitreal anti-VEGF injections (OR=1.235, 95%CI 1.029-1.482, P=0.023) as independent factors associated with ERM formation. The multivariate model achieved an area under the receiver operating characteristic curve of 0.814 after five-fold cross-validation, indicating good predictive performance. ConclusionThe occurrence of ERM in patients with DME is closely associated with longer diabetes duration, a greater number of anti-VEGF injections, increased HRF count, and thicker CMT.