BACKGROUND: Human metapneumovirus (HMPV) and respiratory syncytial virus (RSV) are genetically related viruses and major causes of medically attended acute respiratory illness in children. Research comparing the severity of illnesses resulting from these infections lacks consensus. METHODS: Children younger than 18 years with acute respiratory illness were enrolled through active, prospective surveillance from 2016 to 2020 at 7 US pediatric hospitals and emergency departments (EDs). Clinical information was obtained from parent interviews and medical records. Midturbinate nasal swabs were collected and tested for RSV and HMPV using molecular diagnostic assays at each site. We compared descriptive and clinical features of children with RSV or HMPV and calculated adjusted odds ratios (aOR) for severe outcomes comparing RSV with HMPV. Risk factors for severe outcomes were assessed in children with RSV or HMPV using logistic regression models. RESULTS: A total of 5329 children hospitalized with RSV (n = 4398) or HMPV (n = 931) and 3276 children with RSV-associated (n = 2371) or HMPV-associated (n = 905) ED visits were enrolled. The median age of children hospitalized with RSV was lower than that of children with HMPV (7 months vs 16 months, P < .0001). Children presenting to the ED with RSV-associated acute respiratory illness had higher odds of being hospitalized than children with HMPV (aOR, 1.68; 95% CI, 1.50-1.87), with the highest odds in infants younger than 6 months (aOR, 3.27; 95% CI, 2.53-4.23). Underlying conditions were more than twice as common among infants hospitalized with HMPV (26%) than those with RSV (11%). CONCLUSIONS: Children with HMPV-associated hospitalization tend to be older and more likely to have underlying medical conditions compared with children with RSV-associated hospitalization.