Amyotrophic lateral sclerosis (ALS) is a target for cell-replacement therapies, including therapies based on human neural stem cells (NSCs). These therapies must be first tested in the appropriate animal models, including transgenic rodents harboring superoxide dismutase (SOD1) mutations linked to familial ALS. However, these rodent subjects reject discordant xenografts. In the present investigation, we grafted NSCs from human embryonic spinal cord into the ventral lumbar cord of 2-month-old SOD1-G93A transgenic mice. Animals were immunosuppressed with FK506, FK506 plus rapamycin, FK506 plus rapamycin plus mycophenolate mofetil, or CD4 antibodies. With FK506 monotherapy, human NSC grafts were rejected within 1 week, whereas combinations of FK506 with one or two of the other agents or CD4 antibodies protected grafts into end-stage illness (i.e., more than 2 months after grafting). The combination of FK506 with rapamycin appeared to be optimal with respect to efficacy and simplicity of administration. Graft protection was achieved via the blockade of CD4- and CD8-cell infiltration and attenuation of the microglial phagocytic response from the host. Surviving NSCs differentiated extensively into neurons that began to establish networks with host nerve cells, including alpha-motor neurons. Immunosuppressed animals with live cells showed later onset and a slower progression of motor neuron disease and lived longer compared with immunosuppressed control animals with dead NSC grafts. Our findings indicate that combined immunosuppression promotes the survival of human NSCs grafted in the spinal cord of SOD1-G93A mice and, in doing so, allows the differentiation of NSCs into neurons and leads to the improvement of key parameters of motor neuron disease.