Background: Alpha-fetoprotein (AFP) remains widely used for diagnosing hepatocellular carcinoma (HCC) despite its low sensitivity and specificity. Recently, Annexin A2, a highly expressed protein in HCC and almost undetectable in normal liver cells has been studied as a potential alternative. Objective: To synthesize evidence for the diagnostic accuracy of annexin A2 as an alternative to AFP in the diagnosis of hepatocellular carcinoma. Methods: PubMed, Embase, PsycINFO, and the China National Knowledge Infrastructure (chkd-cnki) databases were searched without time constraints up to 2022. Meta-analysis was conducted using Meta-Disc software. Results: 6 studies were meta-analyzed. The pooled sensitivity and specificity for Annexin A2 were 84% [95% CI :( 80 – 87)], and 78% [95% CI :( 71 – 84)] respectively, while AFP was 70% [95% CI :( 66 – 74)] and 79% [95% CI :( 72 – 85)] respectively. The pooled diagnostic odds ratio was 20.35 [95% CI :( 9.76 – 42.42)] for Annexin A2, and 9.71 [95% CI :( 5.27 – 17.88)] for AFP. The area under the curve (AUC) was 0.88 for Annexin A2 and 0.82 for AFP. Conclusions: Annexin A2 is significantly more sensitive than AFP for HCC diagnosis but less specific. A combination of Annexin A2 and AFP could improve accuracy.