Respiratory syncytial virus (RSV) is the most significant cause of acute respiratory infection (ARI) in children. Despite the common viral aetiology, antibiotics are often prescribed for paediatric ARI, potentially contributing to the growth of antibiotic resistance. The opportunistic pathogen Streptococcus pneumoniae is commonly detected during RSV infections; however the clinical significance of these bacterial co-infections is currently unclear. The role of RSV and S. pneumoniae co-infection was investigated in children under two years presenting with ARI at the emergency department of the Royal Children’s Hospital, Brisbane. Nasopharyngeal aspirates were screened for respiratory viruses and bacteria. Disease severity scores were generated upon study enrolment. In the 58 infants with viral ARI, RSV was the most common virus detected (50%). S. pneumoniae was more frequently detected in RSV infections (64%) compared to other viral infections (46%). The detection of S. pneumoniae was associated with RSV infection after adjustment for confounding factors (adjusted odds ratio, 4.09; 95% confidence interval, 0.95-17.62). Furthermore, infants with RSV and S. pneumoniae co-infections had significantly higher severity scores compared to those with other respiratory viruses and bacteria (p=0.03). These results suggest that RSV and S. pneumoniae may together enhance disease severity during paediatric ARI. Clinical isolates of these pathogens are now being used in an epithelial cell culture model of co-infection, to investigate interactions between RSV, S. pneumoniae and the host. Preliminary data suggests RSV induces a type I interferon response early during co-infection, while S. pneumoniae activates NF-κB signalling. The simultaneous activation of two distinct innate immune pathways by co-infection may lead to synergistic stimulation of downstream processes, such as inflammation, perhaps contributing to enhanced morbidity. Understanding the role of S. pneumoniae during RSV infections is necessary to ensure the effective treatment of paediatric ARI – to answer the question of antibiotic treatment for a cold, perhaps it is time to finesse this old taboo!