Objective <p>To characterize co-infections in children with respiratory syncytial virus (RSV) and evaluate their association with disease severity.</p> Methods <p>We retrospectively analyzed 5, 586 children hospitalized with RSV infection at Tianjin Children’s Hospital between January 2018 and December 2023. Patients were grouped by co-infection status: RSV alone, RSV with viral co-infection, RSV with bacterial co-infection, RSV with <i>Mycoplasma pneumoniae</i> (MP) co-infection, and RSV with multiple co-infections. Demographic characteristics, clinical features, and disease severity were compared across groups.</p> Results <p>Of the 5, 586 patients, 3, 835 had RSV alone, 476 had viral co-infections, 715 had bacterial co-infections, 312 had MP co-infections, and 248 had multiple co-infections. Children with multiple co-infections were older (median 3 vs. 0.5 years; <i>P</i> &lt; 0.05), had longer fever and illness duration, and showed higher rates of severe pneumonia (all <i>P</i> &lt; 0.05). Viral co-infections were more often associated with wheezing and chest retractions, while bacterial and MP co-infections were characterized by fever and cough.</p> Conclusions <p>Co-infections in RSV-infected children were associated with distinct clinical patterns and differences in disease severity. Multiple co-infections were associated with a higher proportion of severe pneumonia and prolonged illness. Identifying co-infection patterns may help detect high-risk patients early and guide individualized management.</p> Clinical trial registration <p>Not applicable.</p>