Gonadotropin-releasing hormone (GnRH) agonists are commonly used in the treatment of uterine leiomyomas, but little is known about their histological and cellular effects on these neoplasms. We examined a cellular proliferation index as determined by the nuclear antigen Ki-67 and proliferating cell nuclear antigen (PCNA) expression, estrogen receptor (ER), and progesterone receptor (PR) expression in 27 leiomyomas from patients treated with the GnRH agonist leuprolide acetate (LA) and compared them with 33 untreated controls. All leiomyomas were removed by myomectomies from premenopausal woman after 2 to 6 months of LA treatment or in the follicular phase of the menstrual cycle in the untreated controls. Histological features examined included cellularity, nuclear atypia, vascular changes (dilated, thickened, or thrombosed vessels), edema, calcification, hemorrhage, necrosis, hyalinization, and mitotic activity. Although no difference was found between GnRH-treated and nontreated groups with respect to most histological features examined, immunohistochemical studies showed a significant decrease in the cellular proliferation index, ER, and PR expression in the LA-treated cases compared with nontreated controls. The cellular proliferation index, ER, and PR expression decreased by 85%, 49%, and 36%, respectively, in the LA-treated group as compared with controls (P < .001). A subset of cases from the LA-treated and nontreated groups were also analyzed with respect to bcl-2 (an inhibitor of apoptosis) expression, and no significant difference between the LA-treated and nontreated groups was observed with both groups showing a strong (> 75% of cells) cytoplasmic staining pattern. Results of this study show that LA treatment of leiomyomas results in a decrease in number of cycling cells.