Hepatic fibrosis represents a process of healing and scarring in response to chronic liver injury. a-Melanocyte-stimulating hormone (a-MSH) is a 13-amino-acid peptide with potent anti-inflammatory effects. We have previously demonstrated that a-MSH gene therapy protects against thioacetamide (TAA)-induced acute liver failure. Therefore, the aim of this study is to investigate whether a-MSH gene therapy possesses antihepatic fibrogenic effect. Liver fibrosis was induced by long-term TAA administration in mice. a-Melanocyte-stimulating hormone expression plasmid was delivered via electroporation after liver fibrosis was established. Our results showed that a-MSH gene therapy attenuated liver fibrosis in TAA-treated mice. Reverse transcription polymerase chain reaction revealed that a-MSH gene therapy attenuated the liver transforming growth factor-b1, collagen a1 and cell adhesion molecule mRNA upregulation. Following gene transfer, the expression of a-smooth muscle actin and cyclooxygenase-2 were both significantly attenuated. Further, a-MSH significantly increased matrix metalloproteinase (MMP), while tissue inhibitors of matrix metalloproteinase (TIMPs) were inactivated. In summary, a-MSH gene therapy reversed established liver fibrosis in mice and prevented the upregulated fibrogenic and pro-inflammatory gene responses after TAA administration. Its collagenolytic effect might be attributed to MMP and TIMP modulation. Hence, a-MSH gene therapy may be an effective therapeutic modality against liver fibrosis with potential clinical use.