Abstract Etoposide‐based treatment is the standard of care for adult HLH in many centers, yet there remains a paucity of data regarding treatment outcomes. We conducted a retrospective study of 23 adults treated with etoposide‐based therapy compared to 10 pediatric HLH cases at a single center. At diagnosis, the median serum ferritin was 20,071 µg/L and 937 µg/L in adults and children, respectively; median sIL‐2r was 14,524 U/mL and 4,478 U/mL. Biochemical response to treatment was high, with 21/23 adults achieving >75% reduction in serum ferritin, but one year survival was only 7/21 compared to 7/10 in pediatric cases.