TANK binding kinase 1 (TBK1) regulates IFN-I, NF-κB, and TNF-induced RIPK1-dependent cell death (RCD). In mice, biallelic loss of TBK1 is embryonically lethal. We discovered four humans, ages 32, 26, 7, and 8 from three unrelated consanguineous families with homozygous loss-of-function mutations in TBK1. All four patients suffer from chronic and systemic autoinflammation, but not severe viral infections. We demonstrate that TBK1 loss results in hypomorphic but sufficient IFN-I induction via RIG-I/MDA5, while the system retains near intact IL-6 induction through NF-κB. Autoinflammation is driven by TNF-induced RCD as patient-derived fibroblasts experienced higher rates of necroptosis in vitro, and CC3 was elevated in peripheral blood ex vivo. Treatment with anti-TNF dampened the baseline circulating inflammatory profile and ameliorated the clinical condition in vivo. These findings highlight the plasticity of the IFN-I response and underscore a cardinal role for TBK1 in the regulation of RCD. Display omitted •Homozygous LoF TBK1 produces systemic autoinflammation, not overt viral disease.•Expressed but inactive TBK1 inhibits IFN-I induction more than no TBK1.•Autoinflammation is driven by TNF-induced cell death caused by dysregulated RIPK1.•Treatment with anti-TNF resolves clinical disease. TBK1 signals activation of antiviral defenses and controls TNF-mediated inflammation. Deletion of TBK1 in mice is embryonically lethal. Humans lacking TBK1 expression survive and have adequate antiviral function. Instead, these individuals suffer from inflammatory pathology driven by sensitivity to TNF-induced cell death that can be effectively treated with anti-TNF therapeutics.