Effective treatment of parapneumonic empyema with multiloculation and septation has been a challenge for clinicians for many years. This study compared the clinical outcomes of video-assisted thoracoscopic surgery (VATS) and intrapleural streptokinase in patients with stage II empyema. This is a retrospective study of 46 patients with parapneumonic empyema with multiloculation and septation in the pleural cavity treated with VATS or streptokinase in Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran, Iran, between January 2018 and January 2021. The main outcome measures of this study were hospital stay, febrile period, days with drainage, and treatment failure. A total of 46 patients were included in this study. Of these, 28 were treated with VATS deloculation, and 18 were treated with streptokinase. The average hospital stay was 2.8 ±1.7 days for the VATS group and 7.5 ±3.5 days for the streptokinase group (p < 0.001). The average days with fever were 1.9 ±0.7 days for the VATS group and 3.0 ±1.64 days for the streptokinase group (p = 0.017). The average days with drainage were 3.0 ±1.6 days for the VATS group and 7.5 ±4.4 days for the streptokinase group (p < 0.001). The success rate was 92.9% for the VATS group and 66.7% for the streptokinase group, which was significantly higher in the VATS group compared to the streptokinase group (p = 0.042). No cases of perioperative mortality occurred. The frequency of adverse events did not differ between study groups (p > 0.05). Our results demonstrated that treatment of empyema with VATS is superior to streptokinase therapy.