Background: Mitsugumin 53 (MG53) plays a protective role against kidney diseases and cardiovascular diseases, but its mechanism of action is unclear. We speculate that the prevention of cardiovascular disease by MG53 may be associated with the inhibition of vascular calcification. This study was performed with the aim of investigating the potential association between the MG53 level and abdominal aortic calcification (AAC) in patients undergoing hemodialysis (HD). Methods: A total of 263 patients undergoing HD and 65 age- and sex-matched healthy individuals were included. The patient serum MG53 level was measured by enzyme-linked immunosorbent assay (ELISA), and the abdominal aortic calcification score (ACCs) was calculated using lateral abdominal radiography parameters. The laboratory and demographic data were collected at baseline. Results: The serum MG53 levels in HD patients were significantly lower than those in healthy individuals [24.9 (IQR: 16.1-40.1) vs 43.5 (IQR: 23.7-74.4) pg/mL, P < 0.001]. In addition, HD patients with AAC presented markedly lower serum MG53 levels than those without AAC [22.0 (IQR: 15.3-32.6) vs 26.9 (IQR: 16.8-44.2) pg/mL, p=0.024]. Furthermore, multiple logistic regression analysis indicated that lower serum MG53 levels, an older age, a longer dialysis vintage, a higher serum total carbon dioxide (TCO2), and a higher serum phosphorus were independent risk factors for AAC in HD patients. Conclusion: Our results demonstrate for the first time a correlation between lower serum MG53 levels and an increased risk of AAC in patients undergoing HD. In addition, an older age, a longer dialysis vintage, the presence of metabolic acidosis and higher serum phosphorus levels are independent risk factors for AAC in HD patients.