Objective – Hepatic inflammation drives the pathogenesis of the chronic diseases such as type 2 diabetes mellitus, insulin resistance, atherosclerosis, and nonalcoholic fatty liver disease (NAFLD). S-[6]-gingerol has been shown to protect against inflammatory insults in various stimulus-induction models. However, it remains unknown whether S-[6]-gingerol protects hepatocytes against cytokine-induced inflammation. Nuclear factor kB (NFkB) is the master regulator of the hepatic inflammatory response. In addition, cyclooxygenase (COX) is among the most important pro-inflammatory mediators and COX-2 is responsible for persistent inflammation. We now explore whether S-[6]-gingerol inhibits IL1β-induced hepatic activation of NFkB and the associated increase in COX2 expression. Methods – HuH7 cells were stimulated with IL1β (8 ng/L) to establish a cytokine-induced cell inflammatory model. Results – Pre-treatment of HuH7 cells with S-[6]-gingerol (100 µM) for 6 h before exposure to IL1β for 3 h significantly attenuated IL1β-induced inflammatory response and oxidative stress, as evidenced by decreased mRNA levels of inflammatory factor IL6, IL8, serum amyloid A1 (SAA1) and reactive oxygen species (ROS) generation and by increased mRNA level of antioxidant protein, DHCR24. In addition, pretreatment with S-[6]-gingerol (100 µM) markedly reduced IL1β-induced COX2 overexpression as well as NFkB activity. Similar to the protective effects of S-[6]-gingerol, both NS-398 (a selective COX2 inhibitor) and PDTC (a selective NFkB inhibitor) suppressed mRNA levels of IL6, IL8 and SAA1. Importantly, PDTC attenuated over-expression of COX2 induced by IL1β. Of particular note, BHT, a ROS scavenger, conferred similar protective effect of S-[6]-gingerol against the IL1β-induced inflammatory response. Conclusions – Together, the findings of the present study demonstrate that S-[6]-gingerol protects HuH7 cells against IL1β-induced inflammatory insults through inhibition of the ROS-activated NFkB/COX2 pathway.