Inborn errors of TLR3-dependent type I IFN immunity in cortical neurons underlie forebrain herpes simplex virus-1 (HSV-1) encephalitis (HSE) due to uncontrolled viral growth and subsequent cell death. We report an otherwise healthy patient with HSE who was compound heterozygous for nonsense (R422*) and frameshift (P493fs9*)RIPK3variants. Receptor interacting protein kinase 3 (RIPK3) is a ubiquitous cytoplasmic kinase regulating cell death outcomes, including apoptosis and necroptosis.In vitro, the R422* and P493fs9* RIPK3 proteins impaired cellular apoptosis and necroptosis upon TLR3, TLR4 or TNFR1 stimulation, and ZBP1/DAI-mediated necroptotic cell death following HSV-1 infection. The patient’s fibroblasts displayed no detectable RIPK3 expression. Following TNFR1 or TLR3 stimulation, the patient’s cells did not undergo apoptosis or necroptosis. Following HSV-1 infection, the cells supported excessive viral growth despite normal induction of antiviral IFN-β and interferon-stimulated genes (ISGs). This phenotype was, nevertheless, rescued by application of exogenous type I IFN. The patient’s human pluripotent stem cell (hPSC)-derived cortical neurons displayed impaired cell death and enhanced viral growth following HSV-1 infection, as did isogenic RIPK3-knockout hPSC-derived cortical neurons. Inherited RIPK3 deficiency therefore confers a predisposition to HSE, by impairing the cell death-dependent control of HSV-1 in cortical neurons independently of type I IFN immunity.