PurposeTo investigate sex-based differences in inflammation-related biomarkers on Spectral-Domain Optical Coherence Tomography (SD-OCT). DesignCross-sectional study. ParticipantsPatients with diabetic macular edema (DME) between February 1, 2019, and March 31, 2023, without intravitreal anti–vascular endothelial growth factor (anti-VEGF) injection within the prior six months. MethodsWe reviewed each patient’s medical record for age, biological sex, race and ethnicity, most recent glycated hemoglobin level (HbA1c), visual acuity (VA), and central macular thickness (CMT). OCT biomarkers that have been found in literature to be associated with inflammation, including disorganization of retinal inner layers (DRIL), retinal hyperreflective foci (HRF), hyperreflective choroidal foci (HCF), subfoveal neuroretinal detachment (SND), and perturbation in retinal nerve fiber layer (RNFL) thickness, ganglion cell layer (GCL) thickness, and inner nuclear layer (INL) thickness were evaluated by graders masked to the clinical characteristics of the patients. We performed multivariable regression analyses with the OCT biomarkers as the outcome variables and sex, age, HbA1c, and CMT as independent variables. Main Outcome MeasuresOCT inflammation-related biomarkers as listed above ResultsFemale patients were on average two years older than male patients (P = 0.041). There were no significant differences in race and ethnicity, HbA1c, VA, or CMT between male and female patients. After controlling for age, HbA1c, and CMT, we found male sex to be associated with more HRF (incidence rate ratio [IRR] = 1.19, 95% confidence interval [CI] = 1.10 – 1.29), more HCF (odds ratio = 2.01, 95% CI = 1.12 – 3.64), and thicker INL (7 μm thicker in males, 95% CI = 2 – 12). Sex was not a significant predictor for either DRIL or SND in the multivariable regression models. Patients with higher HbA1c were more likely to have more HRF (IRR = 1.02 per 1 point increase, 95% CI = 1.00 – 1.04) after controlling for other factors. ConclusionsMale sex was correlated with more inflammation-related biomarkers on OCT including more HRF, more HCF, and thicker INL, after accounting for age, glycemic control, and amount of DME. Further studies are needed to evaluate the potential implications of these sex-based differences for individualized treatment.