Vascular endothelial growth factor (VEGF) gene polymorphisms are associated with the response to pharmaceutical therapy in many cancers. This study aimed to investigate the effects of VEGF gene polymorphisms in esophageal squamous cell carcinoma patients receiving pharmaceutical therapy.This literature-based meta-analysis was performed with keywords related to VEGF gene polymorphisms and clinical response in esophageal squamous carcinoma patients receiving pharmaceutical therapy (including 5-FU, cisplatin, oxaliplatin, and calcium folinate). After a series of bias grading analyses and DerSimonian-Laird method analysis, odds ratios and 95% confidence intervals were calculated to examine the potential relationships. Sensitivity and subgroup analyses were subsequently performed to determine the major causes of heterogeneity.Heterogeneity was dramatically reduced after the removal of one study from the analysis (I2 = 37%, P = 0.19). The remaining studies involved 5-FU-based treatment. The presence of VEGF G-1154A and VEGF-634C/G was found to be correlated with patient response to 5-FU/CDDP-based treatment, whereas VEGF-2549I/D was correlated with response to 5-FU/oxaliplatin-based treatment, and VEGF-936C/T was associated with both 5-FU/CDDP- and 5-FU/oxaliplatin-based treatment response.VEGF gene polymorphisms affect the response of esophageal squamous carcinoma patients receiving pharmaceutical therapy, especially 5-FU-based treatments.