Background: Infection is one of the major morbidity factors after thoracic surgery. Although different prophylactic regimens have been used to prevent this complication, the ideal prophylactic agent, dose and duration of administration remain unknown. Methods: All patients included underwent elective lung resection. 102 selected patients consecutively scheduled for major thoracic surgery were enrolled in this study and randomized into either the cefuroxime group (n=50) or the cefepime group (n=52). Results: Twelve pathologic bacterium strains were isolated in the cefepime group, whereas only 5 pathogenic strains were isolated in the cefuroxime group; the difference was statistically significant (p=0.04). Two empyemas (3.8%) in the cefepime group were noted, while the cefuroxime group showed no cases of empyema (p=0.16). Overall infection rate (pneumonia + bronchopneumonia + empyema) were 14.0% and 26.7% in the cefuroxime and the cefepime groups, respectively (p=0.12). Using chest radiography, pulmonary infiltration was found to be more frequent in the cefuroxime group (p=0.002). Conclusion: Cefuroxime as a prophylactic agent in major thoracic surgical operations was marginally more effective than cefepime, and presented an additional cost advantage.