To determine the association between baseline subfoveal choroidal thickness and short-term response to intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy in diabetic macular edema (DME).Retrospective, consecutive case series.Fifty-three eyes from 42 patients diagnosed with treatment-naïve DME were treated with 3 monthly intravitreal injections of ranibizumab or bevacizumab. Serial enhanced depth imaging optical coherence tomography scans were used to measure subfoveal choroidal thickness and central macular thickness (CMT). Anatomic response (CMT decrease ≥ 50 μm) and functional response (best-corrected visual acuity gain ≥ 1 line) were assessed at 3 months follow-up using univariate and multivariate analyses.After 3 monthly anti-VEGF treatments, subfoveal choroidal thickness decreased significantly (225 μm at baseline, 201 μm at 3 months, P.0001). The anatomic responder group (32 eyes) had a greater baseline choroidal thickness (243 ± 15 μm) than the nonresponder group (21 eyes, 198 ± 13 μm, P = .03). Similarly, the functional responder group (28 eyes) tended to have a greater baseline subfoveal choroidal thickness (239 ± 12 μm) than the nonresponder group (25 eyes, 211 ± 16 μm, P = .08). Multivariate analyses revealed that a greater baseline subfoveal choroidal thickness was associated with a better anatomic (odds ratio = 1.12 for every 10 μm increase, P = .03) and functional response (odds ratio = 8.45 for200 μm vs ≤ 200 μm, P = .008).Baseline subfoveal choroidal thickness may help predict which patients with DME will respond more favorably in the short term to intravitreal anti-VEGF pharmacotherapy. In this study, eyes with a thicker baseline subfoveal choroidal thickness had better short-term anatomic and functional responses.