Introduction: ALS is a fatal neurodegenerative disorder characterized by the selective and progressive deterioration of cortical, brainstem, and spinal cord motor neurons. While the mechanisms underlying neurodegeneration remain elusive, an immune response, dominated by T cells, is evident within the central nervous system (CNS) of ALS patients. Recent evidence suggests a role for regulatory T cells (Tregs) in neuroprotection, neurogenesis and in slowing of disease progression in animal models and in ALS. We investigated the correlation of Treg frequency with disease progression in ALS, and the effects of an IL-2/anti-IL-2 mAb complexes on Treg frequency and disease progression determined in the mSOD1 model. Methods: CD4+CD25hiCD127loFoxP3+ Treg frequency was compared in ALS patients (n = 38) and age-matched controls (n = 40) and correlated with rate of ALS progression (change in revised ALS functional rating scale (ALSFRS-R) per month since diagnosis). IL-2/anti-IL-2 mAb was administered to mSOD1 and wildtype mice and Treg frequency, motor function and survival compared. Results: An elevated Treg response was noted in ALS patients when compared with controls with a higher proportion of naive Tregs in ALS (p = 0.037) as percentage of all CD4 and a higher expression of FoxP3 in memory Tregs in ALS (p = 0.036). These results are in agreement with findings in the early disease phase in the animal model in ALS. We also found a significant inverse correlation between Treg frequency and rate of disease progression measured by ALSFRS-R (r = -0.3, p = 0.034). IL2/anti-IL-2 mAb complex significantly increased Tregs in blood and spleen at endstage, and survival in male SOD1 mice (p = 0.050), but not female. Conclusions: We hypothesise that Tregs are elevated in an attempt to protect the neurons early in disease, but are overtaken by a neurotoxic T effector response later in disease, and that higher Treg levels slow disease progression. Future work will examine potential therapeutic strategies to increase Tregs in ALS.