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PURPOSE To determine the association of aqueous humor cytokine concentrations with long-term treatment response to anti-vascular endothelial growth factor (VEGF) agents in diabetic macular edema (DME). DESIGN Retrospective case series. METHODS Pooled data of aqueous humor cytokine concentrations collected at baseline and 2-month follow-up (2 injections) for treatment-naïve eyes with center-involving DME previously enrolled in a prospective study were reviewed. Subjects receiving intravitreal anti-VEGF injections outside of study protocol as per standard of care were classified into Responders versus Non-responders based on qualitative assessment of optical coherence tomography for persistence of DME at longitudinal follow-up visits. RESULTS Of the 41 eyes, 85% were classified as Responders with a significant decline in baseline central subfield thickness and macular volume (p's < 0.001), and 15% were identified as Non-responders to anti-VEGF therapy over 51.4±18.7 months of follow-up. No significant difference in baseline aqueous humor VEGF concentration was noted, while at 2-month follow-up, the Non-responder group had a significantly higher VEGF concentration compared to the Responder group (451.5±690.9pg/ml versus 113.7±211.4pg/ml; p = 0.02). The Responder group also demonstrated a significant decline from baseline to 2-month follow-up in concentration of intercellular adhesion molecule-1 (p < 0.001), interleukin-10 (p = 0.041), monocyte chemotactic protein-1 (p = 0.046), placental growth factor (p = 0.027), and transforming growth factor-β2 (p = 0.017). CONCLUSIONS Aqueous humor cytokine concentrations serve as an early biomarker for long-term response to anti-VEGF therapy, and may enable more effective treatment regimens that improve anatomical outcomes in eyes with DME.