Background: D-dimer exhibits a certain prognostic value in hepatocellular carcinoma (HCC) patients who underwent hepatectomy and microwave ablation, while its value in estimating the clinical benefit of drug-eluting beads transarterial chemoembolization (DEB-TACE) remains unclear. Hence, this study aimed to investigate the correlation of D-dimer with tumor features, response and survival to DEB-TACE in HCC patients.Methods: Fifty-one HCC patients treated with DEB-TACE were recruited. Their serum samples at baseline and after DEB-TACE were collected and proposed for D-dimer detection by the immunoturbidimetry method.Results: Elevated D-dimer levels were related to a higher Child-Pugh stage (P = 0.013), tumor nodule number (P = 0.031), largest tumor size (P = 0.004), and portal vein invasion (P = 0.050) in HCC patients. Then, patients were classified by the median value of D-dimer, and it was observed that patients with D-dimer >0.7 mg/L achieved a lower complete response rate (12.0% vs. 46.2%, P = 0.007) but a similar objective response rate (84.0% vs. 84.6%, P = 1.000) compared to those with D-dimer <0.7 mg/L. The Kaplan-Meier curve showed that D-dimer >0.7 mg/L (vs. <0.7 mg/L) was related to shorter overall survival (OS) (P = 0.013). Further univariate Cox regression analyses showed that D-dimer >0.7 mg/L (vs. <0.7 mg/L) was related to unfavorable OS [hazard ratio (HR): 5.524, 95% confidence interval (CI): 1.209-25.229, P = 0.027], but it failed to independently estimate OS (HR: 10.303, 95%CI: 0.640-165.831, P = 0.100) in multivariate Cox regression analyses. Moreover, D-dimer was elevated during DEB-TACE therapy (P<0.001).