This study compared the effects of tibolone, a tissue-specific compound for the treatment of climacteric symptoms and the prevention of osteoporosis, with those of conjugated equine estrogens (CEE) with and without medroxyprogesterone (MPA) on bone mineral density and coronary atherosclerosis (CAA) of postmenopausal cynomolgus monkeys. The groups were tibolone [two doses were used, 0.05 mg/kg (LoTib) and 0.2 mg/kg (HiTib)], CEE (0.042 mg/kg), CEE (0.042 mg/kg) plus MPA (0.167 mg/kg given continuously), and a control group given no treatment for 2 yr. Compared with no treatment, bone mineral density was higher by 6.3% (P = 0.0004) in the LoTib group and by 9.5% (P = 0.02) in the HiTib group compared with 4.3% (P = 0.12) for CEE and 4.5% (P = 0.10) for CEE+MPA. Plasma high density lipoprotein cholesterol was reduced by 49% with HiTib and by 34% with LoTib. There were no differences in CAA between control and HiTib (P = 0.60) or LoTib (P = 0.58). CEE and CEE+MPA both reduced CAA by about 62% (CEE vs. control, P = 0.02; CEE+MPA vs. control, P = 0.01). Despite adverse effects of tibolone on plasma lipoprotein concentrations, there was no increase in CAA, suggesting that tibolone is a cardiovascular-safe treatment for climacteric symptoms and the prevention of osteoporosis.