Good vascular pathway is the key to ensure the quality of life in hemodialysis patients. Arteriovenous fistula occlusion lead to insufficient dialysis, increases the probability of hemodialysis complications, even life-threatening. Fibroblast growth factor 21 (FGF21) is increased progressively with a decline of renal function and higher plasma FGF-21 level can be used as a meaningful index to evaluate microinflammation, lipid metabolism and predict dialysis-related complications such as cardiovascular diseases in end stage renal disease patients. This study aimed to investigate the relationship and role of FGF21 in arteriovenous fistula occlusion in our hemodialysis patients cohort. We screened 802 HD patients in Nanjing Zhongda Hospital (n=450) and The First People’s Hospital of Changzhou (n=352) according to a strict inclusion criteria and exclusion criteria. We recorded demographic information, blood data before dialysis and serum FGF21 levels and counted the frequency of arteriovenous fistula occlusion in our hemodialysis cohort. We used bivariate correlation analyses to assess the correlation of the frequency of arteriovenous fistula occlusion with serum FGF21 and other clinical parameters. Stepwise multivariate linear regression analyses were employed to evaluate variables independently associated with the frequency of arteriovenous fistula occlusion. P < 0.05 was considered to be statistically significant. SPSS Software, version 22.0 was used for all statistical analyses. In this cross-sectional study, of 802 hemodialysis patients screened, 76 were eligible. Age of hemodialysis patients was 55.46±15.18 years, and 48 of participants (63.7 %) were male. The median dialysis vintage was 6.4 years (range 0.5 to 23). Serum FGF21 levels were significantly positive associated with the frequency of arteriovenous fistula occlusion (r = 0.321, P = 0.005). In addition, the frequency of arteriovenous fistula occlusion was correlated with the level of hemoglobin(r = -0.277, P = 0.015), the level of albumin (r = -0.269, P = 0.019) and left ventricular mass (r = 0.272, P = 0.018). Variables including FGF 21, hemoglobin, albumin and left ventricular mass and others those well known as promoters of arteriovenous fistula occlusion such as PTH, calcium, phosphorus, glycerin trilaurate and total cholesterol were entered a multivariate linear regression analyses, the result showed that serum FGF21 (β = 0.259, P= 0.022) and left ventricular mass (β = 0.223, P =0.048) were factors independently associated with the frequency of arteriovenous fistula occlusion in hemodialysis patients. We reported for the first time that serum FGF21 and Left ventricular mass were independently associated with arteriovenous fistula occlusion. These findings provide a novel insight about FGF21 on arteriovenous fistula occlusion in hemodialysis patients and may indicate a new therapeutic target for arteriovenous fistula occlusion.