Percutaneous pericardiocentesis represents a salvage procedure in case of cardiac tamponade and diagnostic procedure in chronic pericardial effusion of unknown source. The study aimed to analyze the clinical characteristics of patients subject to pericardiocentesis and the predictors of in-hospital mortality. The study represents a registry that covered consecutive patients undergoing percutaneous pericardiocentesis from 2011 to 2022 in high-volume tertiary reference center. Electronic health records were queried to obtain demographic and clinical variables. The primary endpoint was in-hospital mortality, while secondary endpoint was the need for recurrent pericardiocentesis. Out of 132 456 patients hospitalized in the prespecified period, 247 patients were subject to percutaneous pericardiocentesis (53.9% women; median age of 66 years) who underwent 273 procedures. In-hospital death was reported in 14 patients (5.67%), while recurrent pericardiocentesis in 24 patients (9.72%). Iatrogenic cause was the most common etiology (42.5%), followed by neoplastic disease (23.1%) and idiopathic effusion (14.57%). In logistic regression analysis in-hospital mortality was associated with myocardial infarction (MI)-related etiology (p = 0.001) and recurrent/persistent cardiogenic shock (p = 0.001). Iatrogenic etiology and neoplastic disease seem to be the most common indications for pericardiocentesis, while in-hospital mortality was particularly high in patients with spontaneous tamponade in the course of MI.