Valproic acid is one of anti-convulsant drug and is also potent HDAC inhibitor. We have shown previously that growth of the yeast Saccharomyces cerevisiae in the presence of valproic acid causes an increase in intracellular reactive oxygen species (ROS) and apoptosis in yeast caspase dependent manner. To understand the underlying mechanism of action of valproic acid，we investigate the participation of HDAC to valproic acid-induced apoptosis. We report here that valproic acid induced apoptosis to △rpd3 and △hdal cells as well as wild-type but did not induce apoptosis to SIR2 disrupted mutant when they were cultured with valproic acid. Not only the ROS but also neutral lipids were accumulated in wild-type and △rpd3 and △hda1 cells. In contrast to those cells，ROS and neutral lipid levels were clearly decreased in SIR2 disrupted mutant. Furthermore，annexin-V staining and TUNEL staining are both negative in Asir2 mutant. The level of free fatty acid also changed with SIR2 gene copy number and presence of valproic acid but the mRNA levels of major TAG synthesize enzymes were not affected by them. Based on these observations，we propose that inhibition of SIR2 provide a mechanism for valproic acid-induced apoptosis and could also explain the function of the valproic acid in the lipid metabolism.