<p>Appendicitis is the most common pediatric surgical emergency and one of the most common indications for antibiotic use in hospitalized children. The antibiotic choice differs widely across children's hospitals, and the optimal regimen for perforated appendicitis remains unclear. We conducted a retrospective cohort study comparing initial antibiotic regimens for perforated appendicitis at a large tertiary-care children's hospital. Children hospitalized between January 2011 and March 2015 who underwent surgery for perforated appendicitis were identified by ICD-9 codes with confirmation by chart review. Patients were excluded if they had been admitted ≥48 hours prior to diagnosis, had a history of appendicitis, received inotropic agents, were immunocompromised, or were given an antibiotic regimen other than ceftriaxone plus metronidazole (CTX/MTZ) or an anti-pseudomonal drug (cefepime, piperacillin/tazobactam, ciprofloxacin, imipenem, or meropenem) within the first two days after diagnosis. The primary outcome of interest was post-operative complications, defined as development of an incisional infection or abscess within six weeks of hospital discharge. Of the 353 children who met the inclusion criteria, 252 (71%) received CTX/MTZ and the others received an anti-pseudomonal regimen. A post-operative complication occurred in 37 (14.7%) of the CTX/MTZ group versus 18 (17.8%) of the anti-pseudomonal group. Antibiotic-related complications occurred in 4.4% of children on CTX/MTZ and 6.9% of children on anti-pseudomonal antibiotics (p = 0.32). In a multivariable logistic regression model adjusting for sex, age, ethnicity, and duration of symptoms prior to presentation, the adjusted odds ratio for post-operative complications in children receiving anti-pseudomonal antibiotics was 1.25 (95% confidence interval 0.66-2.40). Post-operative complication rates did not differ for children treated with CTX/MTZ versus a broader-spectrum regimen.</p>