Human herpesvirus-6 (HHV-6), a ubiquitous virus among humans, typically causes acute febrile illness in children, whereas the majority remain asymptomatic. HHV-6 infection can rarely cause encephalitis, with unknown pathogenesis. We hypothesized that inborn single-gene defects may underlie susceptibility to HHV-6 encephalitis in otherwise healthy children. We performed whole-exome sequencing on genomic DNA of a male child diagnosed with acute HHV-6 encephalitis and found a novel homozygous missense variation (NM_016123.4:c.G236A:p.C79Y) in Interleukin-1 receptor-associated kinase 4 (IRAK4), which is involved in the Toll-Interleukin-1 receptor signaling pathway. Sanger sequencing confirmed that both parents and the sibling were heterozygotes. The p.C79Y that affected an evolutionary conserved residue was predicted to be damaging by in silico algorithms. We found that IRAK-4 expression was severely reduced in patient’s leukocytes. There were similar levels of wild-type (WT) and mutant IRAK-4 when transiently over-expressed in HEK293 cells, however mutant IRAK-4 expression was dramatically decreased upon cycloheximide treatment, compared to the WT. This indicated that the p.C79Y might impair IRAK-4 stability. We found that patient’s leukocytes had diminished innate immune responses to various stimuli inducing different Toll-like receptors and cytosolic nucleic acid sensors, compared to the healthy controls. We also generated IRAK4 knockout HEK293 cells by CRISPR-Cas9 genome editing. Transient expression of mutant IRAK-4 had significantly reduced NFκB-dependent luciferase activity, compared to the WT in IRAK4 knockout cells treated with IL-18. Collectively, the p.C79Y impaired both the expression and function of IRAK-4, leading to diminished immune responses against bacterial and viral stimuli in patient’s leukocytes. Overall, this was the first study demonstrating that inborn errors of immunity could underlie isolated acute HHV-6 encephalitis. Our findings also widened the known genotypic and phenotypic spectrum of inherited IRAK-4 deficiency in humans.