Studies of mice and humans suggest a role for loss of the C9orf72 protein in some neurodegenerative disorders: with reduced C9orf72 levels, there is more inflammation mediated by the STING protein in immune and brain cells. Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative disorders that overlap in their clinical presentation, pathology and genetic origin. Autoimmune disorders are also overrepresented in both ALS and FTD, but this remains an unexplained epidemiologic observation(1-3). Expansions of a hexanucleotide repeat (GGGGCC) in theC9orf72gene are the most common cause of familial ALS and FTD (C9-ALS/FTD), and lead to both repeat-containing RNA and dipeptide accumulation, coupled with decreased C9orf72 protein expression in brain and peripheral blood cells(4-6). Here we show in mice that loss ofC9orf72from myeloid cells alone is sufficient to recapitulate the age-dependent lymphoid hypertrophy and autoinflammation seen in animals with a complete knockout ofC9orf72. Dendritic cells isolated fromC9orf72(-/-)mice show marked early activation of the type I interferon response, andC9orf72(-/-)myeloid cells are selectively hyperresponsive to activators of the stimulator of interferon genes (STING) protein-a key regulator of the innate immune response to cytosolic DNA. Degradation of STING through the autolysosomal pathway is diminished inC9orf72(-/-)myeloid cells, and blocking STING suppresses hyperactive type I interferon responses inC9orf72(-/-)immune cells as well as splenomegaly and inflammation inC9orf72(-/-)mice. Moreover, mice lacking one or both copies ofC9orf72are more susceptible to experimental autoimmune encephalitis, mirroring the susceptibility to autoimmune diseases seen in people with C9-ALS/FTD. Finally, blood-derived macrophages, whole blood and brain tissue from patients with C9-ALS/FTD all show an elevated type I interferon signature compared with samples from people with sporadic ALS/FTD; this increased interferon response can be suppressed with a STING inhibitor. Collectively, our results suggest that patients with C9-ALS/FTD have an altered immunophenotype because their reduced levels of C9orf72 cannot suppress the inflammation mediated by the induction of type I interferons by STING.