Inner retinal thinning precedes clinical evidence of retinopathy in prediabetes and diabetes mellitus (DM), and may contribute to retinopathy development and progression. Serum levels of the adipokines leptin and adiponectin are inversely related in the setting of impaired glucose homeostasis, but their potential association with inner retinal thickness is unknown. In this prospective study, both eyes from 24 individuals with prediabetes or type 2 DM (glycated hemoglobin [HbA1c] ≥ 5.7) and 16 controls (HbA1c <
5.7) underwent spectral-domain optical coherence tomography imaging of the macula, and thickness of the nerve fiber layer (NFL) and ganglion cell layer-inner plexiform layer (GCL-IPL) was analyzed in each subfield of the Early Treatment Diabetic Retinopathy Study grid. Serum samples were collected and metabolic factors, including adiponectin and leptin, were measured. Adjusted regression analyses revealed inverse associations of these adipokines with NFL thickness that did not differ between prediabetes/DM and controls, but differential positive associations of adiponectin with GCL-IPL thickness only in the prediabetes/DM group. The results of our pilot study suggest opposing roles for adiponectin and leptin in the retina, similar to their relationship in systemic disease, and suggest that serum adiponectin may represent a potential clinical biomarker for inner retinal thickness in patients with elevated HbA1c.