Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) plays a crucial role in regulating the biosynthesis of mitochondria, which is closely linked to energy metabolism in various tumours. We investigated the regulatory role of PGC-1α in the pathogenesis of hepatocellular carcinoma (HCC).Differences in PGC-1α mRNA levels between normal human liver and HCC tissue were examined by quantitative reverse transcription polymerase chain reaction (qRT-PCR). Knockdown of PGC-1α was done by RNA interference (RNAi) in the human liver cell line L02, and overexpression of PGC-1α was done by transfecting the human hepatocarcinoma cell line HepG2 with adenovirus encoding PGC-1α cDNA (Ad-PGC-1α). Cellular morphological changes were observed via optical and electron microscopy. Cellular apoptosis was determined by Hoechst 33258 staining. In addition, expression levels of 21,400 genes were detected by microarray.PGC-1α expression was significantly lower in HCC compared with normal liver tissues. After knockdown of PGC-1α expression in L02 cells, cells reverted to an immature and de-differentiated morphology exhibiting cancerous tendency. Apoptosis occurred in HepG2 cells after being transfected with Ad-PGC-1α. Microarray analysis showed consistent results.These results suggest that PGC-1α plays an important role in the formation and development of HCC, and that PGC-1α may be a potential therapeutic target for HCC.