Hepatocellular carcinoma (HCC) is a liver tumor that usually arises in patients with cirrhosis. Hepatic stellate cells are key players in the progression of HCC, as they create a fibrotic micro-environment and produce growth factors and cytokines that enhance tumor cell proliferation and migration. We assessed the role of endoplasmic reticulum (ER) stress in the cross-talk between stellate cells and HCC cells. Mice with a fibrotic HCC were treated with the IRE1[alpha]-inhibitor 4[mu]8C, which reduced tumor burden and collagen deposition. By co-culturing HCC-cells with stellate cells, we found that HCC-cells activate IRE[alpha] in stellate cells, thereby contributing to their activation. Inhibiting IRE1[alpha] blocked stellate cell activation, which then decreased proliferation and migration of tumor cells in different in vitro 2D and 3D co-cultures. In addition, we also observed cell-line-specific direct effects of inhibiting IRE1[alpha] in tumor cells.