An increase in the expression of the proinflammatory cytokine tumor necrosis factor alpha (TNF-alpha) has been observed in patients with amyotrophic lateral sclerosis (ALS) and in the mice models of the disease. TNF-alpha is a potent activator of macrophages and microglia and, under certain conditions, can induce or exacerbate neuronal cell death. Here, we assessed the contribution of TNF-alpha in motor neuron disease in mice overexpressing mutant superoxide dismutase 1 (SOD1) genes linked to familial ALS. This was accomplished by the generation of mice expressing SOD1(G37R) or SOD1(G93A) mutants in the context of TNF-alpha gene knock out. Surprisingly, the absence of TNF-alpha did not affect the lifespan or the extent of motor neuron loss in SOD1 transgenic mice. These results provide compelling evidence indicating that TNF-alpha does not directly contribute to motor neuron degeneration caused by SOD1 mutations.