Tibolone is a tissue specific compound used for treatment of climacteric symptoms and prevention of osteoporosis. This study compared the effects of tibolone with conjugated equine estrogens (CEE), with and without medroxyprogesterone acetate (MPA), on the cardiovascular system, mammary gland, and uterus. Surgically-postmenopausal cynomolgus monkeys (n=30/group) were given either no treatment (control), CEE at 0.042 mg/kg, CEE + MPA at 0.167 mg/kg, or tibolone at 0.05 mg/kg (LoTIB) or 0.2 mg/kg (HiTIB). Drugs were given continuously in an atherogenic diet for 2 years. Endpoints included histology and morphometry of endometrium and mammary gland, and immunohistochemical measurement of the proliferation marker Ki67. Treatment with CEE produced marked endometrial thickening and Ki67 expression. This effect was slightly diminished by the addition of MPA. HiTIB but not LoTIB increased endometrial thickness relative to controls; this difference was less than half the effect of CEE+MPA. In contrast to CEE and CEE+MPA, neither LoTIB or HiTIB significantly increased endometrial Ki67 or mammary lobular area. Different letters indicate treatment differences (t-test, P<0.05). These data suggest that tibolone may have advantages over CEE and CEE + MPA regarding endometrial and breast safety.