The aim of this study was to identify factors associated with improved motor function of the lower extremities in response to mesenchymal stem cell (MSC) therapy in patients with ischemic stroke. This study was a post hoc analysis of data from a prospective, open-label, randomized controlled trial of MSC therapy for patients with ischemic stroke patients associated with severe middle cerebral artery territory (STARTING-2 trial). Lower limb motor function was scored based on the lower limb of Fugl-Meyer assessment (FMA-LL) score before MSC therapy and at 3 months after stroke. All FMA-LL changes greater than or equal to six points were considered clinically significant. Univariate and multivariate binary logistic regression models were used to determine possible predictors of clinically significant lower limb motor response to MSC therapy. Twelve (33%) of the thirty-six patients receiving MSC therapy reached a minimal clinically important difference (MCID) of FMA-LL. The two independent factors with the greatest impact on response to MSC therapy for achieving an MCID in FMA-LL score were: (1) the time from stroke onset to MSC therapy, and (2) age ( < 0.05). In addition, obese stroke patients responded better to MSC therapy than stroke patients with normal weight. In conclusion, this post hoc analysis might suggest the need for recruiting stroke patients at younger and early after stroke onset in future clinical trials of MSC therapy for stroke.