Purpose: To correlate serum levels of N-epsilon-carboxy methyl lysine (N-epsilon-CML) with severity of retinopathy, in vivo macular edema and disruption of external limiting membrane (ELM) and photoreceptor ellipsoid zone in type 2 diabetes mellitus (DM). Methods: Consecutive cases of type 2 DM [diabetes mellitus with no retinopathy (No DR) (n = 20); non proliferative diabetic retinopathy (NPDR) with diabetic macular edema (n = 20); proliferative diabetic retinopathy with diabetic macular edema (PDR) (n = 20)] and healthy controls (n = 20) between the ages of 40 and 65 years were included (power of study = 93.8%). In vivo histology of retinal layers was assessed using spectral domain optical coherence tomography. Every study subject underwent macular thickness analysis using the macular cube 512 x 128 feature. Disruption of ELM and photoreceptor ellipsoid zone was graded: grade 0, no disruption of ELM and ellipsoid zone; grade 1, ELM disrupted and ellipsoid zone intact; grade 2, both ELM and ellipsoid zone disrupted. Data were statistically analyzed. Results: The mean levels of N-epsilon-CML were 31.34 +/- 21.23 ng/ml, 73.88 +/- 35.01 ng/ml, 91.21 +/- 66.65 ng/ml, and 132.08 +/- 84.07 ng/ml in control, No DR, NPDR and PDR respectively. N-epsilon-CML level was significantly different between the study groups (control, No DR, NPDR and PDR) (p < 0.001). Mean logMAR visual acuity decreased with increased levels of N-epsilon-CML (p < 0.001). The association of (NCML)-C-epsilon with the grades of disruption was found to be statistically significant (F value = 18.48, p < 0.001). Univariate analysis was done with N-epsilon-CML as a dependent variable. The values of N-epsilon-CML were normalized (log(10)) and were subjected to univariate analysis with fasting blood glucose level, glycosylated hemoglobin, central subfield macular thickness and cube average thickness among the diseased groups (NPDR and PDR) that act as confounders. It was found that none of the variables had significant effect on N-epsilon-CML (fasting blood glucose p = 0.12, HBA1c p = 0.65, central subfield macular thickness p = 0.13, cube average thickness p = 0.19). N-epsilon-CML tends to be a significant and important predictor of grade of ELM and ellipsoid zone disruption in diabetic retinopathy. Conclusions: Increased N-epsilon-CML levels are associated with increased severity of diabetic retinopathy, macular edema and structural changes in macula that is ELM and ellipsoid zone disruption, which serves as a prognosticator of visual outcome. (C) 2016 Elsevier Inc. All rights reserved.