Adipose-derived stem cells (ASCs) are readily accessible and secrete multiple growth factors. Here, we show that ASC transplantation rescues the striatal pathology of Huntington disease (HD) models. ASCs were isolated from human subcutaneous adipose tissue. In a quinolinic acid (QA)-induced rat model of striatal degeneration, human ASCs (1 million cells) were transplanted into the ipsilateral striatal border immediately after the QA injection. In 60-day-old R6/2 mice transgenic for HD, ASCs (0.5 million cells) were transplanted into each bilateral striata. In in vitro experiments, we treated mutant huntingtin gene-transfected cerebral neurons with ASC-conditioned media. In the QA model, human ASCs reduced apomorphine-induced rotation behavior, lesion volume, and striatal apoptosis. In R6/2 transgenic mice, transplantation of ASCs improved Rota-Rod performance and limb clasping, increased survival, attenuated the loss of striatal neurons, and reduced the huntingtin aggregates. ASC-transplanted R6/2 mice expressed elevated levels of peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) and reactive oxygen defense enzymes and showed activation of the Akt/cAMP-response element-binding proteins. ASC-conditioned media decreased the level of N-terminal fragments of mutant huntingtin and associated apoptosis, and increased PGC-1alpha expression. Collectively, ASC transplantation slowed striatal degeneration and behavioral deterioration of HD models, possibly via secreted factors.