Background One of the strongest predictors for osteoporosis is peak bone mass. Interventions to augment peak bone mass have yet to be developed. b-Ecdysone (bEcd), a natural steroid-like compound produced by arthropods to initiate metamorphosis, is believed to have androgenic effects and so may be used to augment bone mass. Questions/purposes The purpose of this study was to use both male and female (1) gonadal-sufficient; and (2) -insufficient mice to investigate sex differences in terms of bone development and structure after bEcd administration.Methods Two-month-old male and female Swiss-Webster mice were randomized to receive either vehicle or bEcd (0.5 mg/kg) for 3 weeks. In a separate experiment to evaluate the effects of bEcd on sex hormone-deficient mice, gonadectomy was performed in male (orchiectomy [ORX]) and female mice (ovariectomy [OVX]). Shamoperated and the ORX/OVX mice were then treated for 3 weeks with bEcd. Primary endpoints for the study were trabecular bone structure and bone strength. Results In male mice, the trabecular bone volume was 0.18 ± 0.02 in the placebo-treated (PL) and 0.23 ± 0.02 in the bEcd-treated group (p \ 0.05 versus PL); and 0.09 ± 0.01 in the ORX group (p \ 0.05 versus PL) and 0.12 ± 0.01 in the ORX + bEcd group. Vertebral bone strength (maximum load) was 43 ± 2 in PL and 51 ± 1 in the bEcd-treated group (p \ 0.05 versus PL); and 30 ± 4 in the ORX group (p \ 0.05 versus PL) and 37 ± 3 in the ORX + bEcd group. In female mice, trabecular bone volume was 0.23 ± 0.02 in PL and 0.26 ± 0.02 in the bEcd-treated group (p \ 0.05 versus PL); and 0.15 ± 0.01 in the OVX group (p \ 0.05 versus PL) and 0.14 ± 0.01 in the OVX + bEcd group. Maximum load of the vertebrae was 45 ± 2 in PL and 48 ± 4 in the bEcd-treated group; and 39 ± 4 in the OVX group (p \ 0.05 versus PL) and 44 ± 4 in the OVX + bEcd group.