Infections due to Human herpes virus 6 (HHV-6) are frequent during early childhood. Usually they have a favorable clinical course. Conversely HHV-6 congenital infections occur in about 1% of neonates and may present with more severe clinical pictures. HHV-6 can be found in lung tissues and bronchoalveolar lavage samples from patients with pneumonia and in immunocompromised patients can cause mild to severe pneumonia. In neonates the role of HHV-6 in the genesis of severe pneumonia is poorly defined still now. We describe a healthy infant with a late onset (15 days of life) severe interstitial pneumonia and heavy HHV-6 genome load, persistently detected in its bronchoalveolar lavage (BAL) fluid. The baby underwent high frequency oscillatory ventilation, hydroxychloroquine, steroids and ganciclovir for six weeks and at 9 months she died. Next generation sequencing of genes known to cause neonatal respiratory insufficiency revealed the presence of a "probably pathogenetic" heterozygous variant in the autosomal recessive DRC1 gene, a heterozygous variant of unknown significance (VUS) in the autosomal recessive RSPH9 gene, and a heterozygous VUS in the autosomal recessive MUC5B gene. HHV-6 infection should be considered in the differential diagnosis of late onset severe respiratory distress in neonates and the co-occurrence of genetic predisposing factors or modifiers should be tested by specific molecular techniques. The intensity of HHV-6 genome load in BAL fluid could be an indicator of the response to the antiviral therapy. This article is protected by