Prevalence of serious bacterial infections in children in countries in western Europe and the USA is low. Antibiotic stewardship aims at a more rational use of antibiotics but information on the frequency of antibiotic prescription to children in emergency departments is scarce. We aimed to quantify and explain variability in antibiotic prescription in children attending European paediatric emergency departments. We did a cross-sectional, observational study of children aged between 1 month and 16 years who presented with fever to one of 28 European emergency departments on one random sampling day per month between Nov 1, 2014, and Feb 28, 2016. The surveyed sites were spread across 11 countries and included 17 academic hospitals with 3000 to up to 80 000 annual visits to their paediatric emergency departments. We determined the proportion of children without comorbidities who received antibiotic prescriptions by country, focus of infection, and type of antibiotic. We then did a detailed analysis of the same population, using a multilevel logistic regression analysis, into the variability in prescriptions across hospitals, focusing particularly on respiratory tract infections and correcting for a combination of result-dependent factors. Random group assignment was done by computer randomisation. Of 5177 children in total, 617 children had comorbidities. Of the 4560 children without comorbidities, 1454 (32%) received antibiotics. This percentage varied from 19% to 64% across countries. Of these 1454 prescriptions issued, 893 (61%) were second-line antibiotics. Antibiotic prescription for respiratory tract infections, the most common infection type, in children without comorbidities was most variable across countries (15-67% for upper respiratory tract infections and 24-87% for lower respiratory tract infections) and was associated with age (odds ratio [OR] 1·51, 95% CI 1·08-2·13), fever duration (OR 1·45, 1·01-2·07), blood concentrations of C-reactive protein (OR 2·31, 1·67-3·19), and chest x-ray results (OR 10·62, 5·65-19·94, for focal abnormalities; OR 3·49, 1·59-7·64, for diffuse abnormalities). After correcting for patient characteristics, diagnostic assessment, and hospital characteristics, antibiotic prescription for respiratory tract infections remained highly variable across emergency departments (standardised antibiotic prescription ratio 0·49-2·04). Antibiotic prescription in European emergency departments is highly variable, with frequent use of second-line antibiotics. To ensure successful antibiotic stewardship initiatives in Europe aimed at reducing unnecessary prescription of antibiotics, variability of prescription across hospitals should be considered, drivers of suboptimal antibiotic prescription at the local level need to be identified, and European guidelines need to be devised. None.