Pigment epithelium-derived factor (PEDF or SERPINF1), a neuroprotective and anti-angiogenic factor, may play an important role in the pathogenesis of diabetic retinopathy (DR). In 416 patients with type 2 diabetes, four polymorphisms in the PEDF SNPs were identified, rs12150053 and rs12948385 in the promoter region, rs9913583 in the 5′-untranslated region, and rs1136287 (Met72Thr) in exon 3. Based on case-control studies, rs12150053 and rs12948385, but not rs9913583 and rs1136287, were significantly associated with DR. A logistic regression analysis revealed that the TC or CC genotype of rs12150053 was a significant risk factor for DR (odds ratio 2.40, p = 0.0004). The GA or AA genotype of rs12948385 was also a significant risk factor for DR. In addition, a significant interaction between the vascular endothelial growth factor ( VEGF) and PEDF SNPs in the susceptibility to DR was found. These results demonstrate that the PEDF gene, in cooperation with the VEGF gene, may contribute to the development of DR.