Neuroinflammation is involved in the pathogenesis of amyotrophic lateral sclerosis (ALS), but only limited data are available on systematic peripheral and central immune cell profiles in ALS. We studied detailed immune profiles of 73 ALS patients and 48 healthy controls (controls) in peripheral blood by fluorescence-activated cell sorting as well as cytokine expression profiles in serum. In a subgroup of 16 ALS patients and 10 controls we additionally studied cerebrospinal fluid (CSF) samples. In peripheral blood, T cell subtypes presented a shift towards pro-inflammatory Th 1 and Th 17 cells whereas anti-inflammatory Th2 and T regulatory cells were decreased. Important players in innate immunity including distinct monocyte (Mo) and natural killer (NK) cell subtypes were changed in ALS patients compared to controls. Pro-inflammatory serum cytokines such as interleukin (IL)-1 beta, IL-6 and interferon-gamma (IFN-gamma) were increased and the anti-inflammatory cytokine IL-10 was decreased. Correlation analysis revealed moderate negative correlations between Th1 and Th17 to the ALS functional rating scale revised (ALSFRS-R) and to forced vital capacity. In CSF samples, no relevant alteration of the immune profile was found. In conclusion, the immune profile in ALS was shifted towards a Th1/Th17 cell-mediated pro-inflammatory immune response and correlated to disease severity and progression. Large prospective studies are needed to confirm these findings. Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease, which affects the upper and lower motoneurons (MN) leading to progressive muscle weakness, paralysis and ultimately death due to respiratory failure. The pathophysiological mechanisms are still unresolved, although increasing knowledge gained in the last two decades. Multiple studies corroborated that numerous pathological processes are involved in MN degeneration and neuroinflammation gained increasing attention and had deemed as a pathological hallmark of ALS 1-3. It is commonly accepted that the non-neuronal neighbors play a significant role in the degenerative process of this vulnerable cell type 4. One of the most impressive pathohistological characteristics during disease progression is activation and increase abundance of microglial cells in the central nervous system (CNS) shown in animal models of ALS 5 as well as in human studies 6-8. Microglial cells are considered to be the resident mononuclear phagocytes in the CNS and can be renewed by bone marrow cells under special circumstances 9,10. It is supposable that specialized peripheral immune cell subsets are attracted to the central compartment to contribute and perpetuate the pathological processes in ALS disease by local inflammation or activation of resident cells. Therefore, neuroinflammation is not limited to the CNS, it needs a systemic inflammatory response to enable the local inflammation. In general, a systemic inflammatory response is very complex, a plethora of different immune cells are involved, diverse cytokines a...