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Background Most perimenopausal and postmenopausal women experience estrogen deficiency–induced vaginal atrophy. However, estrogen replacement therapy has contraindications and side effects, which makes it unsuitable for most women. Cell-free fat extract (CEFFE) has pro-proliferative and proangiogenic tissue regeneration activities. Objectives The purpose of this study was to evaluate the effect of topical application of CEFFE in the vagina and the effect of CEFFE on vaginal keratinocytes. Methods Ovariectomized mice were treated with CEFFE via vaginal topical application for 2 weeks. The vaginal mucosal cell layer number, mucosal thickness, and vaginal collagen volume were determined by histologic analyses. Vaginal mucosa proliferation and lamina propria angiogenesis were evaluated with anti–proliferating cell nuclear antigen and anti-CD31 staining, respectively. For in vitro analysis, VK2/E6E7 cells were administered, increasing the CEFFE concentration. Cell proliferation and cell-cycle distribution were analyzed by Cell Counting Kit 8 assay and flow cytometry, respectively. Mucosal migration was evaluated with a wound-healing assay. The expression of Ki-67 and estrogen-related proteins was detected by western blotting. Results CEFFE-treated mice showed increased mucosal thickness and number of vaginal mucosal cell layers and reduced vaginal atrophy compared to ovariectomized mice. The number of proliferating cell nuclear antigen–positive cells and CD31-positive capillaries also increased. In addition, CEFFE promoted the proliferation and migration of VK2/E6E7 cells, upregulated the expression of Ki-67, and inhibited the expression of estrogen-related proteins and the PI3K/AKT pathway. Conclusions CEFFE prevents estrogen deficiency–induced vaginal atrophy by promoting vaginal mucosal proliferation and increasing neovascularization, but not through the estrogen/estrogen receptor pathway, in an ovariectomized mouse model. [ABSTRACT FROM AUTHOR]