Background: Hemophagocytic lymphohistiocytosis (HLH) is a potentially fatal condition. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) overlaps with HLH. Human-herpesvirus 6 (HHV6) is a common childhood infection that rarely causes neurological complications. HHV6-related HLH/DRESS has only been described in case reports . Procedure: From all admissions to Children’s Minnesota with positive HHV6 the records of a subgroup and additional patients from Israel formed a cohort of patients with HHV6-rlated HLH using HLH-2004 criteria. Results: Of 50 consecutive HHV-6 patients, five (10%) developed HLH/DRESS and with two from other centers a cohort of seven is described (six with HLH and one with DRESS). Four had concurrent viruses as possible pathogenic factors. All had thrombocytopenia, elevated soluble IL2 receptor (CD25), and fever; 6/7 had elevated ferritin, and all 5 evaluated had bone marrow hemophagocytosis. Most (6/7) had CNS involvement, all had liver abnormalities, and most had coagulopathy. One patient with Kabuki syndrome was on gammaglobulin replacement therapy, whereas none of the other patients had immune deficiency. One patient had a heterozygous pathogenic variant of TNFSF13B, with no immunodeficiency. Four required etoposide and dexamethasone therapy, while three were also treated with ganciclovir/valganciclovir. The outcome was excellent (median follow-up almost 6 years) with no neurologic sequelae, recurrent HLH, or need for hematopoietic stem cell transplantation. Conclusions: The high incidence of HHV6-related HLH in admitted patients indicates a strong need for vigilance regarding this condition. HHV6-related HLH has a high rate of CNS manifestations, but the outcome in this group of patients was excellent.