Mutations in the ubiquitously expressed survival motor neuron 1 (SMN1) and superoxide dismutase 1 (SOD1) genes are selectively lethal to motor neurons in spinal muscular atrophy (SMA) and familial amyotrophic lateral sclerosis (ALS), respectively. Genetic association studies provide compelling evidence that SMN1 and SMN2 genotypes encoding lower SMN protein levels are implicated in sporadic ALS, suggesting that SMN expression is a potential determinant of ALS severity. We therefore sought genetic evidence of SMN involvement in ALS by generating transgenic mutant SOD1 mice on an Smn deficient background. Partial genetic disruption of Smn significantly worsened motor performance and survival in transgenic SOD1(G93A) mice. Furthermore, ALS-linked mutant SOD1 expression severely reduced SMN protein levels, but not transcript, in neuronal culture and mouse models from early presymptomatic disease. SMN protein depletion was linked to the nuclear compartment and a physical interaction between SMN and mutant SOD1 was confirmed in mouse spinal cord. Treatment with the environmental toxin paraquat also depleted SMN protein, implicating oxidative stress in the mechanism underlying SMN deficiency in familial ALS and potentially sporadic disease. In contrast, transgenic SOD1(WT) overexpression in SMA type I mice was incapable of modulating SMN protein levels or disease progression. These data establish that SMN deficiency accelerates phenotypic severity in transgenic familial ALS mice, consistent with an enhancing genetic modifier role. We therefore propose that SMN replacement and upregulation strategies considered for SMA therapy may have protective potential for ALS.