OBJECTIVE: Advances in molecular diagnosis have led to increased testing for single and multiviral respiratory infection in routine clinical practice. This study compares outcomes between single and multiviral respiratory infections in children younger than 5 years old admitted to the PICU with respiratory failure. DESIGN: Retrospective, single-center, cohort study. SETTING: Tertiary-care, freestanding children\'s hospital. PATIENTS: Children younger than 5 years old admitted to the PICU with respiratory failure and positive respiratory molecular panel. Children with comorbidity or history of similar infections were excluded. After exclusions, the children were divided into single or multiviral groups. Their demographics and PICU outcomes were compared and analyzed. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Four hundred seventy-seven children with respiratory failure tested positive on respiratory panel, out of which 432 had single and 45 had multiple viruses. Children with multiple viruses had a longer PICU stay (4.5 d) compared with the single viral group (3 d; p < 0.002). Multiviral infections were associated with higher utilization of central line (odds ratio, 2.4; 95% CI, 1.3-4.6; p = 0.008) but not with the need of invasive ventilation requirement or cardiovascular dysfunction. Further analysis among invasively ventilated patients showed multiviral infections resulted in higher association of prolonged ventilation (> 7 d) (odds ratio, 3.4; 95% CI, 1.2-9.4; p = 0.01) and bacterial lower respiratory tract infection confirmed by quantitative bronchoalveolar lavage (odds ratio, 2.1; 95% CI, 1.1-11.2; p = 0.03). Infections with human rhinovirus/Enterovirus, Adenovirus, parainfluenza, and influenza formed a significantly larger proportions of cases (p = 0.00089) as multiviral infections compared with individual infections. CONCLUSIONS: Multiviral infections were associated with longer PICU stay, with prolonged mechanical ventilation, with bacterial lower respiratory infections, and with central line requirement. Certain common viruses resulted in higher percentages of PICU admission as multiviral infections.