Objective: This study compared outcomes in patients with solid tumor treated for pericardial effusion with surgical drainage vs. interventional radiology (IR) percutaneous drainage and compared incidence of paradoxical hemodynamic instability (PHI) between cohorts. Summary Background Data: Patients with advanced-stage solid malignancies may develop large pericardial effusions requiring intervention. PHI is a fatal and underreported complication that occurs following pericardial effusion drainage. Methods: Clinical characteristics and outcomes were compared between patients with solid tumors who underwent surgical drainage or IR percutaneous drainage for pericardial effusion from 2010 to 2020. Results: Among 447 patients, 243 were treated with surgical drainage, of which 27 (11%) developed PHI, compared with 7 of 204 patients (3%) who were treated with IR percutaneous drainage (P=0.002); overall incidence of PHI decreased during the study period. Rates of reintervention (30-day: 1% vs. 4%; 90-day: 4% vs. 6%, P=0.7) and mortality (30-day: 21% vs. 17%, P=0.3; 90-day: 39% vs. 37%, P=0.7) were not different between patients treated with surgical drainage and IR percutaneous drainage. For both interventions, OS was shorter among patients with PHI than among patients without PHI (surgical drainage, median [95% confidence interval] OS, 0.89 mo [0.33–2.1] vs. 6.5 mo [5.0–8.9], P<0.001; IR percutaneous drainage, 3.7 mo [0.23–6.8] vs. 5.0 mo [4.0–8.1], P=0.044). Conclusions: With a coordinated multidisciplinary approach focusing on prompt clinical and echocardiographic evaluation, triage with bias toward IR percutaneous drainage than surgical drainage and post-intervention intensive care resulted in lower incidence of PHI and improved outcomes.