Hepatocellular carcinoma (HCC) is an aggressive subtype of liver cancer with few effective treatments and the underlying mechanisms that drive HCC pathogenesis remain poorly characterized. Identifying genes and pathways essential for HCC cell growth will aid the development of new targeted therapies for HCC. Using a kinome CRISPR screen in three human HCC cell lines, we identified transformation/transcription domain-associated protein (TRRAP) as an essential gene for HCC cell proliferation. TRRAP has been implicated in oncogenic transformation, but how it functions in cancer cell proliferation is not established. Here, we show that depletion of TRRAP or its co-factor, histone acetyltransferase KAT5, inhibits HCC cell growth via induction of p53- and p21-independent senescence. Integrated cancer genomics analyses using patient data and RNA-sequencing identified mitotic genes as key TRRAP/KAT5 targets in HCC, and subsequent cell cycle analyses revealed that TRRAP- and KAT5-depleted cells are arrested at G2/M phase. Depletion of TOP2A, a mitotic gene and TRRAP/KAT5 target, was sufficient to recapitulate the senescent phenotype of TRRAP/KAT5 knockdown. CONCLUSION: Our results uncover a role for TRRAP/KAT5 in promoting HCC cell proliferation via activation of mitotic genes. Targeting the TRRAP/KAT5 complex is a potential therapeutic strategy for HCC.