Bromodomain-containing 8 (BRD8), which belongs to the histone acetyl transferase (HAT) complex, functions as a driver in colorectal cancer. However, the role of BRD8 and its related regulatory mechanisms in hepatocellular carcinoma (HCC) remain unexplored. In this study, we found that the level of BRD8 mRNA in HCC was prominently higher than that in nontumor tissues. Furthermore, immunohistochemistry analysis indicated that BRD8 protein expression was upregulated in HCC compared to noncancerous tissues. The positive expression of BRD8 was closely associated with HBV infection, a tumor size ≥5 cm and an advanced TNM stage. Moreover, HCC patients with an elevated expression of BRD8 had an obvious poorer survival rate. Functionally, BRD8 knockdown markedly reduced the proliferation of Hep3B and Huh7 cells. Depletion of BRD8 obviously induced the apoptosis of HCC cells. Conversely, BRD8 overexpression promoted the proliferation and apoptosis resistance of Huh7 cells. Lysine acetyltransferase 5 (KAT5) expression was significantly upregulated in HCC tissues. In addition, BRD8 knockdown obviously reduced the level of KAT5 protein and the mRNA expression of KAT5-induced genes in both Hep3B and Huh7 cells. KAT5 knockdown showed similar effects as BRD8 silencing on HCC cell proliferation and apoptosis. The expression of miR-876-3p was downregulated and inversely correlated with the BRD8 mRNA level in HCC tissues. The expression of BRD8 protein in HCC cells was reduced by the overexpression of miR-876-3p and enhanced by the knockdown of miR-876-3p. A luciferase reporter assay demonstrated that BRD8 was a direct target of miR-876-3p. Notably, in HCC cells, the ectopic expression of miR-876-3p inhibited proliferation and induced apoptosis. In conclusion, BRD8, which was negatively regulated by miR-876-3p, facilitated proliferation and inhibited apoptosis in HCC cells by modulating KAT5.Copyright © 2020. Published by Elsevier Inc.