Attaining and maintaining optimal “dry weight” is one of the principal goals during maintenance hemodialysis (MHD). Recent studies have shown a close relationship between Na+ load and serum vascular endothelial growth factor-C (VEGF-C) levels; thus, we aimed to investigate the role of VEGF-C as a candidate biomarker of hypervolemia. Physical examination, basic laboratory tests, N-terminal pro b-type natriuretic peptide (NT-ProBNP), echocardiography, and bioimpedance spectroscopy data of 3 groups of study subjects (euvolemic MHD patients, healthy controls, and hypervolemic chronic kidney disease [CKD] patients) were analyzed. Research data for MHD patients were obtained both before the first and after the last hemodialysis (HD) sessions of the week. Data of 10 subjects from each study groups were included in the analysis. Serum VEGF-C levels were significantly higher in hypervolemic CKD versus in MHD patients both before the first and after the last HD sessions (P = .004 and P = .000, respectively). Healthy controls had serum VEGF-C levels similar to and higher than MHD patients before the first and after the last HD sessions of the week (P = .327 and P = .021, respectively). VEGF-C levels were correlated with bioimpedance spectroscopy results (r2 0.659, P = .000) and edema (r2 0.494, P =0.006), but not with ejection fraction (EF) (r2 −0.251, P = .134), blood pressures (systolic r2 0.037, P = 0.824, diastolic r2 −0.067, P = .691), and NT-ProBNP (r2 −0.047, P = .773). These findings suggest that serum VEGF-C levels could be a potential new biomarker of hypervolemia. The lack of correlation between VEGF-C and EF may hold a promise to eliminate this common confounder. Further studies are needed to define the clinical utility of VEGF-C in volume management.