BACKGROUND: The current use of prophylactic antibiotics for lung cancer surgery requires modification in aging individuals with impaired lung function. A sustained-release formulation of azithromycin (AZM-SR) could help resolve some of these challenges with its sustained antibacterial and anti-inflammatory effects. The aim of this study was to examine the safety and efficacy of AZM-SR in lung cancer surgery as well as its anti-inflammatory effect. METHODS: Fifty patients were included in the study, and AZM-SR was administered 1 day prior to the surgery. The clinical course, including postoperative complications, was monitored, and the concentration of AZM, bacterial culture, and inflammatory cytokine levels of resected lung specimens were evaluated. RESULTS: No side effects related to AZM-SR were observed. Five cases of postoperative pneumonia (10%) were observed; technical issues were involved in 3 cases. All patients recovered well. Four cases showed positive bacterial culture upon lung tissue examination; however, this was not significantly correlated with postoperative complications. A negative correlation was observed between AZM concentration in lung tissue and interleukin-6 (IL-6) expression. CONCLUSIONS: Prophylactic utilization of AZM-SR in lung cancer surgery seems feasible. The anti-inflammatory effect of AZM might contribute additional beneficial effects in the perioperative management of lung cancer surgery.