Despite the health risks for postmenopausal women, the indications and ideal candidates for hormone replacement therapy remain unclear. The present study used ovariectomized rats to examine the safety and effects of the Chinese herbal formula Menoprogen (MPG), which is prescribed for menopausal syndrome. Daily oral MPG (1000 mg/kg body weight) for 2 weeks significantly recovered uterine and adrenal gland atrophy and restored serum estradiol, estrone and progesterone levels that were decreased in rats by bilateral ovariectomy. However, yeast two-hybrid and nuclear receptor cofactor assays showed that MPG did not bind estrogen receptors alpha (ERalpha) and beta, and immunohistochemical staining revealed that unlike 17beta-estradiol, MPG did not stimulate the protein expression of ERalpha, progesterone receptor, c-jun and c-fos in the uterus. No side effects of MPG were confirmed in vivo. These findings suggest that MPG would be useful for treating women with premenopausal and postmenopausal syndromes.