Long-term use of valproic acid (VA), a well-tolerated anticonvulsant agent widely used for treating epilepsia, has been recently shown to inhibit histone deacetylases, which in turn are involved in the regulation of the expression of estrogen receptor alpha (ERalpha) by suppressing gene transcription. Because estrogens are known to increase cell proliferation of human endometrial tumors, in this study we investigated whether treatment with VA may increase the proliferative response of human endometrial adenocarcinoma cells to 17-beta-estradiol through induction of ERalpha. The results clearly show that VA, at concentrations of clinical interest, significantly enhanced the proliferative activity exerted by 17-beta-estradiol in the endometrial adenocarcinoma Ishikawa cell line. Moreover, in these cells treatment with VA resulted in increased ERalpha gene expression. Similar effects of VA on cell proliferation were also observed in an ERalpha-positive breast cancer cell line (MCF-7). These findings indicate that VA might favor proliferation of estrogen-dependent human tumors.