Mice that overexpress the human Cu,Zn superoxide dismutase-1 mutant G93A develop a delayed and progressive motor neuron disease similar to human amyotrophic lateral sclerosis (ALS). Most current studies of therapeutics in these mice to date have involved administration of agents long before onset of symptoms, which cannot currently be accomplished in human ALS patients. We examined the effects of the manganese porphyrin AEOL 10150 (manganese [III] tetrakis[N-N'-diethylimidazolium-2-yl]porphyrin) given at symptom onset and found, in three separate studies, that it extended the survival after onset up to 3.0-fold. Immunohistochemical analysis of spinal cord for SMI-32, an abundant protein in motor neurons, indicated better preservation of motor neuron architecture, less astrogliosis (glial fibrillary acidic protein), and markedly less nitrotyrosine and malondialdehyde in porphyrin-treated spinal cords relative to vehicle-treated mice. These results show that the catalytic antioxidant AEOL 10150 provides a pronounced therapeutic benefit with onset administration and is, therefore, a promising agent for the treatment of ALS.