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Background: Hepatocellular carcinoma (HCC) is the third leading cause of cancer mortality worldwide. Increasing evidence indicates a close relationship between HCC and the human microbiota. Herein, we reviewed the important potential of the human microbiota as a diagnostic biomarker of HCC.Data sources: Several innovative studies have investigated the characteristics of the gut and oral micro- biomes in patients with HCC and proposed that the human microbiome has the potential to be a diag- nostic biomarker of HCC. Literature from February 1999 to February 2019 was searched in the PubMed database using the keywords microbiota or microbiome or microbe and liver cancer or hepato- cellular carcinoma, and the results of clinical and experimental studies were analyzed. Results: Specific changes occur in the human microbiome of patients with HCC. Moreover, the gut mi- crobiome and oral microbiome can be used as non-invasive diagnostic biomarkers for HCC. Furthermore, they also have certain diagnostic potential for precancerous diseases of HCC. The diagnostic potential of the blood microbiota and ascites microbiota in HCC will be gradually discovered in the future. Conclusions: The human microbiome is valuable to the diagnosis of HCC and provides a novel strategy for targeted therapy of HCC. The human microbiome may be widely used in the diagnosis, treatment and prognosis for multiple system diseases or cancers in the future.