Tibolone is a synthetic agent with tissue-specific effects, including an antiresorptive effect on bone. Clinical trials have documented prevention of bone loss in postmenopausal women; a daily oral dose of 2.5 mg has generally been used. The present study evaluated tibolone therapy over 2 years with daily doses of 0.3, 0.625, 1.25, or 2.5 mg of tibolone as compared with placebo in 770 generally healthy women who were 1 to 4 years past menopause and who had normal bone density for their age. All of them took supplemental calcium carbonate as well in a daily dose of 500 mg. Bone mineral density (BMD) was measured in the lumbar spine and right proximal femur by dual-energy x-ray absorptiometry for up to 2 years. The patient population was drawn from two identically designed randomized, placebo-controlled, dose-finding studies. A total of 519 women completed the 2-year studies. Tibolone led to a progressive increase in spinal and total hip BMD over 2 years of treatment in all doses except 0.3 mg. Hip BMD was maintained by the 0.3-mg dose. Only doses of 1.25 or 2.5 mg daily progressively increased BMD at the femoral neck. Differences in mean percentage of change from baseline in spinal and total hip BMD were significant for all dose groups compared with placebo. The rise in BMD at the lumbar spine over baseline, with 1.25 or 2.5 mg daily, was 2.0 to 2.6% at 2 years, a statistically significant and clinically meaningful effect. Increasing BMD was not limited to the first year of tibolone therapy. All tibolone doses except the lowest were associated with decreased serum osteocalcin levels, whereas in placebo recipients osteocalcin increased over baseline. Comparable reductions in bone-specific alkaline phosphatase were noted in patients given 1.25 and 2.5 mg of tibolone. Total cholesterol levels decreased in all tibolone dose groups, but declines in high-density lipoprotein cholesterol, triglycerides, and apolipoprotein A-1 seemed to be dose-related. All doses of tibolone were generally well tolerated during the 2 years of administration. No deep venous thrombosis or pulmonary embolism was observed. Hot flashes were less frequent with tibolone therapy than with placebo and were at their lowest with the 2.5-mg dose. Average body weight changes were similar in the actively treated and placebo groups. Endometrial hyperplasia was comparably frequent in the two groups. Vaginal bleeding became less prevalent with continued tibolone treatment. A 1.25-mg daily dose of tibolone is recommended for preventing osteoporosis. The ability of this drug to dose-dependently increase BMD in the lumbar spine and total hip should allow individualized antiresorptive treatment for postmenopausal women according to their clinical response.