Background:The present study aimed to systematically evaluate the diagnostic value of an isoform of alpha-fetoprotein (AFP), AFP-L3, for early hepatocellular carcinoma (HCC) by a meta-analysis.Methods:Diagnostic reports of AFP-L3% in early HCC were searched in the PubMed, Web of Science, Cochrane Library, and Embase databases up to December 2019. The retrieved literature was reviewed, and eligible articles were selected. Data were extracted from the eligible articles, and the risk of bias was evaluated according to the Quality Assessment of Diagnostic Accuracy Studies scale. Statistical analyses were conducted by MetaDiSc1.4 and RevMan5.3 software. The sensitivities, specificities, and diagnostic odds ratios were pooled. The summary receiver operating characteristic curve was drawn, and the area under the curve was calculated.Results:Six studies with acceptable quality were included in the meta-analysis involving 2447 patients. No threshold effect was observed among the 6 studies, but there was obvious heterogeneity. The pooled sensitivity, specificity, and positive and negative likelihood ratios of AFP-L3% for the diagnosis of early HCC were 0.34 (95% CI 0.30–0.39, P < .0001), 0.92 (95% CI 0.91–0.93, P < .0001), 4.46 (95% CI 2.94–6.77, P = .0033), and 0.71 (95% CI 0.61–0.82, P = .0004), respectively. The diagnostic odds ratio was 6.78 (95% CI 4.02–11.44, P = .0074). The the area under the curve of the summary receiver operating characteristic was 0.755 (95% CI 0.57–0.94).Conclusion:AFP-L3% has high specificity but low sensitivity for diagnose early HCC, suggesting that AFP-L3% is more valuable for excluding HCC in conditions with elevated AFP than for diagnosing early HCC. In addition, a hypersensitive detection method can improve the diagnostic accuracy of AFP-L3% for early HCC.