Objective To explore the efficacy, safety and prognostic factors of drug-eluting bead-transarterial chemoembolization (DEB-TACE) in treatment of the patients with early and middle stage hepatocellular carcinoma (HCC). Methods Twenty-six early and middle stage HCC patients receiving DEB-TACE treatment were enrolled in this prospective cohort study. Modified response evaluation criteria in solid tumors (mRECIST) was used to evaluate the efficacy of DEB-TACE treatment. The deadline for follow-up was Dec. 20, 2017, and the progression free survival (PFS) and overall survival (OS) were recorded. Multivariate logistic regression model and Cox proportional regression model were used to analyze the factors affecting the efficacy and prognosis. Results A total of 32 DEB-TACE treatment were performed in 26 patients. Treatment-related adverse events were recorded in 31 DEB-TACE treatments. Perioperative pain frequency was 15 times (48.4%), including mild pain 10 times (32.3%) and moderate pain 5 times (16.1%); and fever frequency was 10 times (32.3%) and gastrointestinal reaction was 5 times (16.1%). Within 3 months of DEB-TACE treatment, the overall response rate (ORR) was 65.4% (17/26), and disease control rate (DCR) was 84.6% (22/26). Compared with the patients with maximum diameter of tumors ≥ 50 mm, the patients with maximum diameter of tumors<50 mm had a significantly higher ORR (92.3%[12/13] vs 38.5%[5/13], P=0.013). Compared with the patients with Barcelona stage B, the patients with Barcelona stage A had a significantly higher ORR (81.3%[13/16] vs 40.0%[4/10], P=0.031). The follow-up ranged from 2.9 to 20.0 months (median 7.2 months), median PFS was 11.9 months (95% CI 5.0-18.9 months), and median OS was 14.6 months (95% CI 9.9-19.2 months). Multivariate logistic regression revealed that tumor maximum diameter ≥ 50 mm was an independent predictor of poor ORR (P=0.036). Cox proportional regression model analysis showed that no clinicopathological characteristics were independent predictors of PFS or OS. Conclusion DEB-TACE treatment is an effective and safe method for early and middle stage HCC patients, and maximum diameter of tumor ≥ 50 mm can be used as an independent prognostic biomarker.