Approximately 185 million people are or have been infected with Hepatitis C virus ( HCV) worldwide. HCV causes not only severe liver problems but also extra hepatic manifestations, such as insulin resistance (IR) and type 2 diabetes mellitus (T2DM) . Peroxisome proliferator-activated receptor gamma coactivator 1 alpha ( PGC-1α) is a transcription factor coactivator that plays an essential role in cellular energy metabolism, and cumulative studies link the abnormal high expression of PGC-1α to IR and T2DM. Besides, HCV hijacks host lipid metabolism for its infection, and the very low density lipoprotein (VLDL) secretory pathway is exploited to facilitate HCV assembly and secretion; coincidently, PGC-1α is reportedly important in VLDL assembly through a downstream factor. Therefore, we hypothesize that, on the one hand, HCV infection results in WT-PGC-1α/L-PGC-1α high expression which will further lead to T2DM, on the other hand, WT-PGC-1α and L-PGC-1α demonstrate proviral functions in HCV production through the regulation of VLDL. Combining previous studies in the literature with our current findings, we elaborate the relationship between HCV and PGC-1α, and discuss the mechanism how HCV infection upregulates PGC-1α.