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Globally, a chronic-hepatitis B virus (HBV) infection is the leading cause of hepatocellular carcinoma (HCC). The transcription factor hypoxia-inducible factor 1 (HIF1) is often elevated in HCC, including HBV-associated HCC. Previous studies have suggested that the expression of the HIF1 subunit, HIF1α, is elevated in HBV-infected hepatocytes; however, whether HIF1 activity affects the HBV lifecycle has not been fully explored. We used a liver-derived cell line and ex vivo cultured primary hepatocytes as models to determine how HIF1 affects the HBV lifecycle. We observed that HIF1 elevates HBV RNA transcript levels, core protein levels, core protein localization to the cytoplasm, and HBV genome replication. Attenuating the transcription activity of HIF1 blocked HIF1-mediated effects on the HBV lifecycle. Our studies show that HIF1 regulates various stages of the HBV lifecycle in hepatocytes and could be a therapeutic target for blocking HBV replication and the development of HBV-associated diseases. • Characterized the effect of HIF1 on the HBV lifecycle in a liver cell line and cultured primary hepatocytes. • HIF1 elevates the levels of HBV RNA transcripts, nucleocapsids and genome replication. • HIF1 elevates HBV core protein levels and core protein localization to the cytoplasm. • Attenuating the transcription activity of HIF1 blocked HIF1-mediated effects on the HBV lifecycle. • HIF1 could be a therapeutic target for blocking HBV replication and the development of HBV-associated diseases. [ABSTRACT FROM AUTHOR]