Histone deacetylase inhibitors (HDACIs) can inhibit proliferation, induce cell cycle arrest and stimulate apoptosis of cancer cells. Our purpose was to investigate the antiproliferative effects of a novel HDACI, apicidin, on the Ishikawa endometrial cancer cell line, the SK-OV-3 ovarian cancer cell line and normal human endometrial epithelial cells. Endometrial and ovarian cancer cells were treated with various concentrations of apicidin, and the effects on cell growth, cell cycle, apoptosis and related measurements were investigated. MTT assays showed that all endometrial and ovarian cancer cell lines were sensitive to the growth inhibitory effect of apicidin, although normal endometrial epithelial cells were viable after the treatment with the same doses of apicidin that induced the growth inhibition of endometrial and ovarian cancer cells. Cell cycle analysis indicated that their exposure to apicidin decreased the proportion of cells in S-phase and increased the proportion in G0/G1 and/or G2/M phases of the cell cycle. Induction of apoptosis was confirmed by Annexin V staining of externalized phosphatidylserine and loss of the transmembrane potential of mitochondria. This induction occurred in concert with the altered expression of p21WAF1, p27KIP1, p16, cyclin A, and E-cadherin. Furthermore, apicidin treatment of these cell lines increased acetylation of H3 and H4 histone tails. These results suggest that apicidin exhibits the antiproliferative effects through selective induction of genes related to cell growth, malignant phenotype, and apoptosis. The findings raise the possibility that apicidin may prove particularly effective in the treatment of endometrial and ovarian cancers.