As of August 2022, clusters of acute severe hepatitis of unknown etiology in children have been reported from 35 countries, including the United States1,2. Previous studies have found human adenoviruses (HAdVs) in the blood from cases in Europe and the United States3-7, although it is unclear whether this virus is causative. Here we used PCR testing, viral enrichment based sequencing, and agnostic metagenomic sequencing to analyze samples from 16 HAdV-positive cases from October 1, 2021 to May 22, 2022, in parallel with 113 controls. In blood from 14 cases, adeno-associated virus 2 (AAV2) sequences were detected in 93% (13 of 14), compared to 4 (3.5%) of 113 controls (P