BACKGROUND: The foot fat pad (FFP) bears body weight and may become a source of foot pain during aging. This study investigated the regenerative effects of autologous adipose tissue-derived mesenchymal stem cells (AT-MSCs) in the FFP of rats. METHODS: Fat tissue was harvested from a total of 30 male Sprague-Dawley rats for isolation of AT-MSCs. The cells were cultured, adipogenic differentiation was induced for 1 week, and the AT-MSCs were labeled with fluorescent dye before injection. AT-MSCs (5 × 10(4) in 50 µL of saline) were injected into the second infradigital pad in the right hindfoot of the rat of origin. Saline only (50 µL) was injected into the corresponding fat pad in the left hind paw of each rat. Rats (n = 10) were euthanized at 1, 2, and 3 weeks, and the second infradigital fat pads were dissected for histologic examination. RESULTS: The fluorescence-labeled AT-MSCs were present in the foot pads throughout the 3-week experimental period. On histologic testing, the area of fat pad units (FPUs) in the fat pads that received AT-MSC injections was greater than that in the control fat pads. Although the thickness of septae was not changed by AT-MSC injections, the density of elastic fibers in the septae was increased in the fat pads with implanted AT-MSCs. CONCLUSION: In this short-term study, the implanted AT-MSCs largely survived and might have stimulated the expansion of individual FPUs and increased the density of elastic fibers in the FFP in this rat model. CLINICAL RELEVANCE: These data support the development of stem cell therapies for age-associated degeneration in FFP in humans.