The interleukin‐6–type cytokine oncostatin M (OSM) acts via the Janus kinase/signal transducer and activator of transcription pathway as well as via activation of mitogen‐activated protein kinases and is known to critically regulate processes such as liver development and regeneration, hematopoiesis, and angiogenesis, which are also determined by hypoxia with the hypoxia‐inducible factor 1α (HIF1α) as a key component. Here we show that treatment of hepatocytes and hepatoma cells with OSM leads to an increased protein level of HIF1α under normoxic and hypoxic conditions. Furthermore, the OSM‐dependent HIF1α increase is mediated via Janus kinase/signal transducer and activator of transcription 3 and mitogen‐activated protein kinase kinase/extracellular signal‐regulated kinase 1/2 pathways. OSM‐mediated HIF1α up‐regulation did not result from an increase in HIF1α protein stability but from increased transcription from the HIF1α gene. In addition, we show that the OSM‐induced HIF1α gene transcription and the resulting enhanced HIF1α protein levels are important for the OSM‐dependent vascular endothelial growth factor and plasminogen activator inhibitor 1 gene induction associated with several diseases. Conclusion: HIF1α levels increase significantly after treatment of hepatocytes and hepatoma cells with OSM, and HIF1α contributes to OSM downstream signaling events, pointing to a cross‐talk between cytokine and hypoxia signaling in processes such as liver development and regeneration. (HEPATOLOGY 2009.)