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Abstract Background Vascular endothelial growth factor (VEGF) is a signal protein, induces cell proliferation, and enhances the permeability of the endothelial cells. VEGF-A gene is highly polymorphic, with different near-gene variants at varied frequencies linked with altered VEGF protein expression, type 2 diabetes mellitus (T2DM) susceptibility, and associated microvascular complications. The present study aimed to investigate the role of two genetic variants of VEGF-A, − 583C > T (rs3025020) and + 936 C/T (rs3025039), for predicting mixed microvascular complications in T2DM. This case–control study was performed on 26 T2DM patients with mixed microvascular complications and 26 apparently healthy individuals, as a control group. Clinical, neurological, funds examinations, and biochemical laboratory investigations were conducted on all groups. The serum level of VEGF-A was measured using ELISA. Genotyping of VEGF-A was performed by real-time PCR allelic discrimination system. Results Serum level of VEGF-A was significantly increased in T2DM with mixed complications. T allele of VEGF-A rs3025020 showed higher frequency among T2DM patients with mixed complications than in control group [OR 2.67; 95% CI 1.03–6.91; p = 0.04], while CT genotype and T allele of VEGF-A rs3025039 had a high frequency in mixed complication group [OR 4.08; 95% CI 1.32–17.44; p = 0.01 and OR 4.02; 95% CI 1.52–10.63; p = 0.004, respectively]. Conclusion VEGF-A increased the level contributed in the pathogenesis of mixed diabetic microvascular complications. T allele of VEGF-A rs3025020, CT genotype, and T allele of VEGF-A rs3025039 had the highest frequency in mixed diabetic microvascular complications, so they were considered risk genes for mixed diabetic microvascular complications.