Histone deacetylase 6 (HDAC) 6 is a regulatory factor in the endocrine traffic network that controls growth factor receptor stability. Histone deacetylase 6 expression and its pathogenic role in the uterine leiomyoma have not been studied. Here, we demonstrated that there was a consistent pattern of increasing HDAC6 and estrogen receptor (ER) α expression in leiomyoma samples. For all individual cases, expression of HDAC6 in the normal myometrium or leiomyoma positively correlated with ERα expression. The spearman's rho (ρ) was .53 (P = .008) between HDAC6 and ERα in normal myometrium and, more significantly, the spearman rho was .80 (P < .001) between HDAC6 and ERα in leiomyoma. In ELT-3 leiomyoma cells, silencing HDAC6 expression substantially reduced ERα expression, lowered estrogen response, and inhibited ELT-3 cell growth. Our results, taken together, are the first to provide experimental evidence suggesting that HDAC6 may be an essential molecular therapeutic target in controlling leiomyoma growth.