Hepatic stellate cells (HSC) play a key role in liver fibrogenesis. Activation of PPARγ and inhibition of fibrogenic molecules are potential strategies to block HSC activation and differentiation. A number of natural products have been suggested to have antifibrotic effects for the de-activation and de-differentiation of HSCs. The purpose of this study was to investigate the in vitro effects of capsaicin on HSC de-activation and de-differentiation. The results demonstrated that capsaicin induced quiescent phenotype in GRX via PPARγ activation. Significant decrease in COX-2 and type I collagen mRNA expression was observed in the first 24 h of treatment. These events preceded the reduction of TGF-β1 and total collagen secretion. Thus, capsaicin promoted down-regulation of HSC activation by its antifibrotic and anti-inflammatory actions. These findings demonstrate that capsaicin may have potential as a novel therapeutic agent for the treatment of liver fibrosis.