ZAP-70 deficiency constitutes an autosomal recessive inherited form of T+B+NK+ Combined Immunodeficiency (CID). Clinical features consistent with severe CID (SCID) could be present. Absence of CD8+T cells but normal number of non-functional CD4+T cells are phenotypic characteristics. After primary infection, human Herpesvirus-6 (HHV-6) induces a lifelong latent infection in humans. Even though it is a neurotropic virus encephalomyelitis is an uncommon clinical manifestation in immunocompetent individuals. We describe a 11 month-old girl with a ZAP-70 deficiency, presented as a SCID. The patient presented T lymphopenia, extremely low CD8+T-cells (0.25%-6/mm³) and low naïve CD4+CD45RA+ (18%) lymphocytes. Zap-70 protein expression was undetectable by flow cytometry. Mutational analysis by Sanger sequencing identified a homozygous frameshift variant (NM_001079 c.1510_1522 delAAGTGGTACGCAC) in ZAP-70 gene affecting the kinase domain, confirming the diagnosis. The patient developed in the course of her illness many meningeal signs that required several brain image studies and cerebral spinal fluid (CSF) punctures to reach the diagnosis of encephalopathy due to a HHV-6 infection. To sum up, we present an unusual Zap-70-deficient SCID patient who developed a life threatening CNS HHV-6 infection (seizures and progressive deterioration of the sensorium). HHV-6 is a certain possibility of severe CNS infection in primary immunodeficiencies (PID) and should be searched thoroughly, especially when neurological manifestations are present.