Objective To systematically evaluate the diagnostic efficacy of circulating tumor DNA (ctDNA) in hepatitis B viral hepatocellular carcinoma (HBV-HCC), and to study the clinical value of ctDNA. Methods The databases of PubMed, Embase, Web of Science, and Cochrane Library database were retrieved systematically from the establishment of the database to April 26, 2021. The characteristic information of literatures and the original data such as the sensitivity, specificity, and area under curve (AUC) of the receiver operating characteristic (ROC) curve were extracted. A meta-analysis was conducted by applying RevMan 5.3 and Stata 15.0 software. The combined sensitivity, combined specificity, positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio (OR) were calculated, ROC curve was plotted and the AUC was calculated, Deck’s funnel chart to assess publication bias, the Fagan diagram to test the diagnostic efficiency. Results Finally, 16 studies involving 3 744 patients were enrolled in this study, of which 1 852 were HBV-HCC patients, and 1 892 were HBV-infected patients without HCC. The meta-analysis results showed that ctDNA had a pooled sensitivity of 0.85 [95%CI (0.78, 0.90)], a specificity of 0.74 [95%CI (0.63, 0.83)], a diagnostic OR of 15.98 [95%CI (10.65, 23.99)], and the AUC of ROC was 0.87 [95%CI (0.84, 0.90)] in the diagnosis of HBV-HCC. The pooled sensitivity, specificity, diagnostic OR, and the AUC of ROC for ctDNA combined with AFP in the diagnosis of HBV-HCC were 0.86 [95%CI (0.80, 0.90)], 0.79 [95%CI (0.68, 0.87)], 22.69 [95%CI (13.64, 37.76)], and 0.90 [95%CI (0.87, 0.92)]. Meta-regression analysis found that the heterogeneity came from other non-covariate factors. The Fagan chart showed that while HBV-HCC was diagnosed by liquid biopsy-based on ctDNA, the probability of being diagnosed with hepatocellular carcinoma was 77%, if HBV-HCC was excluded, the probability of having the corresponding disease was 17%. Deek’s test showed no obvious publication bias (P>0.05). ConclusionsThe ctDNA can diagnose HBV-HCC with high sensitivity, specificity and accuracy, and can be used as a promising circulating biomarker in the early diagnosis of HBV-related HCC. The combination of ctDNA in serum and AFP is beneficial to improve the diagnostic accuracy of HBV-HCC.