Free fatty acid induction of inflammation and cell death is an important feature of nonalcoholic steatohepatitis (NASH) and has been associated with disruption of the endoplasmic reticulum and activation of the unfolded protein response (UPR). After chronic UPR activation, the transcription factor CHOP (GADD153/DDIT3) triggers cell death; however, the mechanisms linking the UPR or CHOP to hepatoceullular injury and inflammation in the pathogenesis of NASH are not well understood. Using HepG2 and primary human hepatocytes, we found that CHOP induces cell death and inflammatory responses after saturated free fatty acid exposure by activating NF-κB through a pathway involving IRAK2 expression, resulting in secretion of cytokines IL-8 and TNFα directly from hepatocytes. TNFα facilitates hepatocyte death upon exposure to saturated free fatty acids, and secretion of both IL-8 and TNFα contribute to inflammation. Of interest, CHOP/NF-κB signaling is not conserved in primary rodent hepatocytes. Our studies suggest that CHOP plays a vital role in the pathophysiology of NASH by induction of secreted factors that trigger inflammation and hepatocellular death via a signaling pathway specific to human hepatocytes.