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The purpose of this study was to determine whether aqueous levels of vascular endothelial growth factor (VEGF) and pigment epithelium-derived factor (PEDF) are associated with developments of serous retinal detachment (SRD) secondary to branch retinal vein occlusion.We recruited 102 patients with branch retinal vein occlusion and 10 controls. We divided patients into two groups according to optical coherence tomography images of the macula. Forty-six of 102 patients showed SRD defined as being subretinal fluid accumulation with low reflectivity, and the remaining 56 patients presented only cystoid macular edema (CME) defined as being hyporeflective intraretinal cavities. We measured the extent of vascular leakage (disk areas) by digital fluorescein angiography and evaluated the retinal ischemia defined as capillary nonperfusion. Aqueous concentrations of VEGF and pigment epithelium–derived factor were measured by enzyme-linked immunosorbent assay and compared between the two groups.The incidence of major branch retinal vein occlusion was higher in the SRD group (38 of 46, 83%) than in the CME group (32 of 56, 66%, P = 0.01). The incidences of ischemic vein occlusion and macular ischemia was similar between the SRD group (18 of 46 and 20 of 46) and the CME group (20 of 56 and 24 of 56), whereas vascular leakage areas were larger in the SRD group than in the CME group (P = 0.02). Aqueous VEGF levels were higher in the SRD group than in the CME group (P < 0.001), whereas aqueous pigment epithelium–derived factor levels were similar. Vascular endothelial growth factor levels were positively correlated with pigment epithelium–derived factor levels (P < 0.001).Our results indicate that excessive increase in vascular permeability because of VEGF upregulation may contribute to the development of SRD secondary to branch retinal vein occlusion.