Abstract:AIM: To investigate correlation of clinical, optical coherence tomography (OCT), and immunohistochemistry (IHC) in idiopathic and secondary epiretinal membrane (ERM). METHODS: Retrospective review of patients undergoing pars plana vitrectomy with membrane peeling (PPV-MP). Excised membranes were evaluated by IHC staining for glial fibrillary acidic protein (GFAP), α-smooth muscle actin (α-SMA), cytokeratin, pigment, and fibrosis grading. Pre-operative and post-operative OCTs, and clinical follow-up information at least 3mo were collected. RESULTS: This study analyzed 104 eyes of 104 patients, of whom 83 (79.8%) had idiopathic ERM (iERM) and 21 (20.2%) had secondary ERM (sERM). Mean age at the time of surgery was 67.3±10.5y. OCT demonstrated greater foveal distortion (P=0.012), intraretinal (IR) spaces (P=0.009), and ellipsoid zone (EZ) discontinuity (P=0.022) in sERMs. Poorer pre-operative BCVA for all cases correlated with foveal distortion (P=0.011), loss of parallelism (P=0.014), IR spaces (P=0.027), and EZ disruption (P=0.012). Poorer post-operative BCVA for all cases was associated with foveal distortion (P=0.027). GFAP was expressed in nearly all ERMs (99%). Pigment was expressed more in sERM (61.9%) compared with iERM (21.7%; P=0.005) and associated with poorer post-operative BCVA (P=0.035) and ERM dehiscence (P=0.008). Fibrosis severity correlated with poorer pre-operative BCVA (P=0.027). GFAP intensity correlated with longer symptom duration (P=0.002). CONCLUSION: The high prevalence of many cell types not distinguished for iERM versus sERM suggests a common pathway of formation with local influences rather than an etiologic cell type or substrate location.