BACKGROUND: Human rhinovirus/enterovirus (HRV/ENT) infections are commonly identified in children with acute respiratory infections (ARIs), but data on their clinical severity remain limited. OBJECTIVES: We compared the clinical severity of HRV/ENT to respiratory syncytial virus (RSV), influenza A/B (FLU), and other common respiratory viruses in children. PATIENTS/METHODS: Retrospective study of children with ARIs and confirmed single positive viral infections on mid-turbinate swabs by molecular assays. Outcome measures included hospital admission and, for inpatients, a composite endpoint consisting of intensive care admission, hospitalization >5 days, oxygen requirements or death. RESULTS: A total of 116 HRV/ENT, 102 RSV, 99 FLU, and 64 other common respiratory viruses were identified. Children with single HRV/ENT infections presented with significantly higher rates of underlying immunosuppressive conditions compared to those with RSV (37.9% versus 13.6%; P < 0.001), FLU (37.9% versus 22%; P = 0.018) or any other single viral infection (37.9% versus 22.5%; P = 0.024). In multivariable analysis adjusted for underlying conditions and age, children with HRV/ENT infections had increased odds of hospitalization compared to children with RSV infections (OR 2.6; 95% CI 1.4, 4.8; P < 0.003) or FLU infections (OR 3.0; 95% CI 1.6, 5.8; <0.001) and increased odds of severe clinical disease among inpatients (OR 3.0; 95% CI 1.6,5.6; P = 0.001) when compared to those with FLU infections. CONCLUSIONS: Children with HRV/ENT had a more severe clinical course than those with RSV and FLUA/B infections and often had significant comorbidities. These findings emphasize the importance of considering HRV/ENT infection in children presenting with severe acute respiratory tract infections.