BACKGROUND: Human adenovirus (HAdV) is commonly associated with acute respiratory illnesses (ARI) in children and is also frequently co-detected with other viral pathogens. We compared clinical presentation and outcomes in young children with HAdV detected alone vs co-detected with other respiratory viruses. METHODS: We used data from a multicenter, prospective, viral surveillance study of children seen in the emergency department and inpatient pediatric settings at seven US sites. Children less than 18 years old with fever and/or respiratory symptoms were enrolled between 12/1/16 and 10/31/18 and tested by molecular methods for HAdV, human rhinovirus/enterovirus (HRV/EV), respiratory syncytial virus (RSV), parainfluenza (PIV, types 1-4), influenza (flu, types A-C), and human metapneumovirus (HMPV). Our primary measure of illness severity was hospitalization; among hospitalized children, secondary severity outcomes included oxygen support and length of stay (LOS). RESULTS: Of the 18,603 children enrolled, HAdV was detected in 1,136 (6.1%), among whom 646 (56.9%) had co-detection with at least one other respiratory virus. HRV/EV (n = 293, 45.3%) and RSV (n = 123, 19.0%) were the most frequent co-detections. Children with HRV/EV (aOR = 1.61; 95% CI = [1.11-2.34]), RSV (aOR = 4.48; 95% CI = [2.81-7.14]), HMPV (aOR = 3.39; 95% CI = [1.69-6.77]), or >/= 2 co-detections (aOR = 1.95; 95% CI = [1.14-3.36]) had higher odds of hospitalization compared to children with HAdV alone. Among hospitalized children, HAdV co-detection with RSV or HMPV was each associated with higher odds of oxygen support, while co-detection with PIV or influenza viruses was each associated with higher mean LOS. CONCLUSIONS: HAdV co-detection with other respiratory viruses was associated with greater disease severity among children with ARI compared to HAdV detection alone.