Human herpesviruses-6 and -7 (HHV-6 and 7) are considered uncommon causes of central nervous system infection and may occasionally cause encephalitis in young infants, however, the clinical syndrome and incidence are not well defined. In immunosuppressed hosts, reactivation is associated with a worse outcome such as encephalitis, hepatitis, or graft rejection. In immunocompetent hosts, this persistent infection is generally of no consequence. We report 4 cases of immunocompetent critically ill children, affected by HHV-6 and -7 encephalitis, admitted to our Pediatric Intensive Care Unit. In three patients, herpesvirus polymerase chain reaction in blood and cerebrospinal fluid was positive for HHV- 6, while one patient was positive for HHV-7. In our cases, a typical clinical picture of viral infection was not present but neurological symptoms were predominant. In all 4 children, neurological involvement rapidly regressed after acyclovir therapy. In this report, we offer evidence that HHV-6 and -7 primary infections can cause several clinical manifestations, such as encephalitis, also in immunocompetent hosts. In our experience, children with neurological symptoms suggestive of viral encephalitis should be fully investigated for these two viruses.