SETD8/KMT5A knockout using CRISPR/Cas9 inhibited tumor growth (p < 0.01) in vivo.<h4>Conclusions</h4>SETD8/KMT5A overexpression was associated with poor prognosis and was an independent prognostic factor in hepatocellular carcinoma. Here, KMT5A is linked to hepatocellular carcinoma.