Objective · To explore the effect of Let-7a regulating bone mesenchymal stem cells (BMSC) proliferation on osteoporosis. Methods · Eightweek-old healthy female mice were obtained to establish ovariectomy (OVX) and sham animal models. Micro-CT was applied to detect the parameters of bone density, bone volume fraction and trabecular number of both groups two months after surgery. MTT was used to detect the proliferation ability of BMSC in OVX and sham groups. Real-time PCR was used to detect the expression of Let-7a. After up-regulating or down-regulating the expression of Let-7a, MTT was also used to detect the proliferation ability of BMSC. Results · The results of Micro-CT showed that compared with sham group, bone density, bone volume fraction and trabecular number of OVX group were significant declined. Increased adipogenic ability and impaired osteogenic ability was found in BMSC in OVX group, in comparison with sham group. The proliferation ability of BMSC in OVX group was declined compared with sham group. The expression of Let-7a in OVX group was significantly increased compared with Sham group. The proliferation ability of BMSC was decreased when the expression of Let-7a was up-regulated, while increased when its expression was down-regulated. Conclusion · High expression of Let-7a inhibit the proliferation of BMSC, which may result in the pathogenesis of postmenopausal osteoporosis.