Background: Existing data, which compare the outcomes of surgical pericardial window operation versus pericardiocentesis in patients with significant pericardial effusion indicated for drainage, are limited and not enough to guide the best management option for these patients. Here, we examined the results for individuals who were treated for pericardial effusion with either pericardiocentesis or a surgical pericardial window. Patients and methods: A retrospective, single-center, observational, comparative study of patients who were admitted to the Cardiothoracic Surgery Department, Tanta University. Between January 2018 and December 2022. 200 individuals with pericardial window surgery or pericardiocentesis were identified using hospital registries. Results: Both surgical pericardial window and pericardiocentesis were beneficial in this research for treating patients with substantial pericardial effusion, and there was an insignificant difference in overall mortality between the two procedures. Nevertheless, there were disparities between the two approaches, with more patients requiring further treatments if the fluid was drained with pericardiocentesis, as well as a higher rate of residual pericardial effusion and re-accumulation of pericardial effusion in the pericardiocentesis group. Conclusion:  The surgical pericardial window operation is superior to pericardiocentesis in the management of patients with significant pericardial effusion indicated for drainage with regard to the incidence and amount of residual effusion and as regards to the occurrence of pericardial effusion re-accumulation; however, both techniques are safe, life-saving and effective approaches for the management of patients with instances of cardiac tamponade and severe pericardial effusion.