Objective: Endometrial stromal sarcoma (ESS) is a gynecological malignancy with few therapeutic options. Up-regulated histone deacetylase (HDAC) 2 was observed in ESS patients. The HDAC inhibitor SAHA reduced ESS cell growth by inhibiting mTOR. The PI3K/Akt/mTOR signaling cascade, vital to cancer growth is a critical target in cancer therapy. This study aimed at investigating if HDACs interact with the PI3K signaling in ESS pathogenesis and thus might serve as targets for ESS therapy. Method: Tissue microarrays were used to determine HDAC expression in ESS specimens. Western blots revealed protein expression levels of HDACs and PI3K related molecules in two independent ESS and one control cell lines (ESS-1, MES-SA and HESC). Results: Elevated HDAC1 and 2 levels were found in ESS tissues and cell lines. Increased cell growth and Akt/mTOR cascade hyperactivation were detected in ESS cells. SAHA reduced growth of all cells, and induced cell death in ESS cells. SAHA reduced phosphorylated 4EBP1 in all cells, but only inhibited activation of Akt and p70S6k in ESS-1 cells. Conclusion: HDACs are linked to PI3K signaling during ESS pathogenesis. SAHA reduced cell growth via inhibiting PI3K/Akt/mTOR components suggesting that a combination of SAHA with PI3K inhibitors might be effective in treating ESS.