Background: YKL-40, a glycoprotein, is associated with inflammatory conditions, including endothelial dysfunction and atherosclerosis. This study aimed to assess the significance of YKL-40 levels in the serum in a hemodialysis (HD) population and investigate their connection to cardiovascular disease (CVD) development. Methods: A case-control study was conducted from August 2022 to January 2023, involving 80 participants (30 patients with CVD and chronic HD, 30 patients with chronic HD without CVD, and 20 apparently healthy individuals). Laboratory assessments encompassed kidney function tests (creatinine and urea), serum sodium and potassium levels, Troponin I, highly sensitive C-reactive protein (Hs-CRP), and serum YKL-40 concentrations measured using ELISA. Incidences of CVD events among the patients were documented. Results: Significantly elevated YKL-40 levels were observed in HD patients with CVD compared to HD patients without CVD and the control group (p < 0.001). There was also a significant increase in YKL-40 in HD patients without CVD compared to the control group (p < 0.001). Additionally, a significant positive correlation was found between YKL-40 and Troponin I (p < 0.001) in HD patients, both with and without CVD. ROC analysis indicated that YKL-40, with a cutoff value of >928.4 ng/ml, could effectively differentiate between HD patients with and without CVD. Both univariate and multivariate analyses demonstrated that troponin I and YKL-40 were associated with an increased likelihood of CVD among HD patients. Conclusion: YKL-40 is a biomarker associated with inflammation, and it shown to have elevated levels among patients with HD. Among those patients, our study shows that YKL-40 increases CVD risk.