To assess the impact of early antibiotic use in the treatment of asthma exacerbation without comorbid bacterial infection on clinical outcomes and resource use.A total of 48 743 children between 3 months and 15 years hospitalized for asthma exacerbation with no evidence of bacterial infection who were treated with intravenous corticosteroids and inhaled short-acting β-agonists.Cases were retrospectively identified from an inpatient database, including records from >1000 hospitals in Japan. Those who received antibiotics during the first 2 days of hospitalization were included in the early treatment group, whereas those who had antibiotic therapy after the first 2 days or not at all were considered the untreated group. The primary outcome was the mean length of hospital stay. Secondary outcomes included hospitalization cost, risk of mechanical ventilation, risk of readmission, and risk of probiotic use because of antibiotic-associated diarrhea.A total of 19 866 (40.8%) of 48 743 eligible children were included in the early treatment group. This group had a longer hospital stay (average difference: 0.21 days; 95% confidence interval [CI]: 0.17 to 0.25), higher cost of hospitalization (mean difference: $83.5; 95% CI: 62.9 to 104), and higher rate of probiotic use (rate ratio: 2.01; 95% CI: 1.81 to 2.23). The risk of 30-day readmission did not significantly differ between the 2 groups. The risk of mechanical ventilation was similar or slightly higher in the early treatment group, depending on the statistical model.Early antibiotic treatment in asthma exacerbation is associated with several negative outcomes without clear clinical benefit: slightly longer hospital stay, increased health care costs, increased risk of probiotic use, and possibly higher risk of mechanical ventilation.Despite the known association of viral respiratory tract infections with asthma exacerbations in children, there continues to be high rates of antibiotic use for pediatric asthma exacerbations in developed countries. There have been conflicting results of studies examining the utility of early antibiotic use, particularly macrolide therapy, for asthma exacerbation. With this study, the authors add to evidence illustrating that risks of antibiotic therapy outweigh benefits in the treatment of asthma exacerbation without evidence of bacterial infection.