Background: Prolonging post-operative antibiotic treatment beyond 3 days does not seem to reduce the incidence of post-operative abscess formation or wound infection after surgery for complicated appendicitis. The route of administration seems to be based on an empirical basis. Using enteral antibiotics could reduce length of stay and reduce overall costs. We aimed to examine whether treatment with enteral antibiotics during the first three post-operative days is non-inferior to intravenous antibiotics regarding intra-abdominal abscess formation or wound infection after surgery for complicated appendicitis. Methods: A retrospective study of adult patients having surgery for complicated appendicitis within a period of 32 months in the Capital Region of Denmark. Primary outcome was the incidence of post-operative abscess formation, and secondary outcome was wound infections, both within 30 days of surgery. Route of antibiotic administration for the first three post-operative days was registered for all patients. Results: A total of 1141 patients were included in the study. The overall risk of developing an intra-abdominal abscess was 6.7% (95% CI 5.2%; 8.1%), and the risk of wound infection was 1.2% (95% CI 0.6%; 1.8%). In a multivariate intention-to-treat analysis, patients treated post-operatively with enteral antibiotics had an odds ratio of 0.78 (95% CI 0.41; 1.45, p = 0.429) for developing an intra-abdominal abscess and an odds ratio of 0.86 (95% CI 0.17; 4.29, p = 0.851) for developing a wound infection compared to patients treated post-operatively with intravenous antibiotics. Conclusion: Treatment with enteral antibiotics was non-inferior compared to treatment with intravenous antibiotics during the first 3 days after surgery for complicated appendicitis.