This study evaluated the efficacy and tolerability of risedronate once a week (35 mg and 50 mg) compared with risedronate 5 mg once daily in women with osteoporosis. We conducted a randomized, double-blind, active-controlled, 2-year study; the primary efficacy assessment was performed after 1 year. Subjects were women aged 50 years or older who had been postmenopausal for at least 5 years, with either a bone mineral density (BMD) T-score of -2.5 or lower (lumbar spine or proximal femur) or a T-score lower than -2 and at least one prevalent vertebral fracture. Subjects received risedronate 5 mg once daily, 35 mg once a week or 50 mg once a week. All subjects also received 1 g daily of elemental calcium supplementation and supplemental vitamin D if the baseline serum levels were low. The primary efficacy measure was percent change in lumbar spine BMD at 12 months. A total of 1,456 women were randomized and received medication; 1,209 (83%) women completed 12 months. The mean percent change (SE) in lumbar spine BMD after 12 months was 4.0% (0.2%) in the 5 mg daily group, 3.9% (0.2%) in the 35 mg group, and 4.2% (0.2%) in the 50 mg group; each once-a-week treatment was determined to be as effective as the daily treatment. Outcomes of the secondary efficacy measurements and safety assessments were also similar in all 3 groups after 12 months. Risedronate 35 mg and 50 mg once a week provide the same efficacy and safety as the daily 5 mg regimen; therefore, the lower dose, 35 mg once a week, is considered optimal for women with postmenopausal osteoporosis who desire a once-a-week regimen.