Aim: Identification of critically ill children upon presentation to the emergency department (ED) is challenging, especially when resources are limited. The objective of this study was to identify ED risk factors associated with serious clinical deterioration (SCD) during hospitalisation in a resource-limited setting. Methods: A retrospective case–control study of children less than 18 years of age presenting to the ED in a large, freestanding children's hospital in Peru was performed. Cases had SCD during the first 7 days of hospitalisation whereas controls did not. Information collected during initial ED evaluation was used to identify risk factors for SCD. Results: A total of 120 cases and 974 controls were included. In univariate analysis, young age, residence outside Lima, evaluation at another facility prior to ED presentation, congenital malformations, abnormal neurologic baseline, co-morbidities and a prior paediatric intensive care unit admission were associated with SCD. In multivariate analysis, age < 12 months, residence outside Lima and evaluation at another facility prior to ED presentation remained associated with SCD. In addition, comatose neurological status, hypoxaemia, tachycardia, tachypnoea and temperature were also associated with SCD. Conclusions: Many risk factors for SCD during hospitalisation can be identified upon presentation to the ED. Using these factors to adjust monitoring during and after the ED stay has the potential to decrease SCD events. Further studies are needed to determine whether this holds true in other resource-limited settings.