Background <p>Cognitive impairment in individuals with Major Depressive Disorder (MDD) may have an association with the levels of Vascular Endothelial Growth Factor (VEGF). However, the relationship between peripheral VEGF levels and cognitive function in MDD patients remains unclear and has not been thoroughly investigated in a clinical setting.</p> Methods <p>In this case-control study, we recruited 60 patients diagnosed with MDD according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria (33 males and 27 females, mean age 41.17 ± 13.32 years) and 60 healthy controls (28 males and 32 females, mean age 37.20 ± 11.93 years). Serum VEGF levels were measured using an ELISA kit, and cognitive performance was assessed using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Group differences were analyzed using analysis of variance (ANOVA)/analysis of covariance (ANCOVA), and associations were assessed using Pearson’s correlation. This study was approved by the Institutional Review Board of Suzhou Guangji Hospital.</p> Results <p>Following adjustment for variables such as gender, age, BMI, and other potential confounding factors, it was observed that the serum VEGF levels in individuals with depression were significantly reduced compared to those in the corresponding healthy control group (F = 4.55, <i>p</i> = 0.04). Within the depressive patient cohort, serum VEGF levels negatively correlated with attention scores (<i>r</i>=-0.32, <i>p</i> = 0.01) and RBANS total scores (<i>r</i>=-0.28, <i>p</i> = 0.03). Conversely, no such correlations were observed in the healthy control group (attention scores: <i>r</i> = 0.19, <i>p</i> = 0.15; RBANS total scores: <i>r</i>=-0.03, <i>p</i> = 0.82).</p> Conclusions <p>Our study suggests that reduced serum VEGF levels may contribute to cognitive impairment in MDD, warranting further investigation into its potential role as a biomarker and therapeutic target.</p>