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Abstract Background While numerous, most described cases of myocarditis and pericarditis following COVID-19 vaccination are mild and self-limited. We present two cases of life-threatening cardiac tamponade following COVID-19 vaccination. Methods Two cases of cardiac tamponade in temporal association with COVID-19 vaccination were reviewed Results Case 1 : 75-year-old male with rheumatoid arthritis admitted with chest pressure and hypotension 2 days after his 1st dose of Pfizer-BioNTech COVID-19 vaccine. Pericardiocentesis removed 275 ml of exudative effusion with 14,140 nucleated cells/ml. Fluid bacterial and fungal cultures were negative; cytology was inconsistent with malignancy. He had no Epstein-Barr virus (EBV) or cytomegalovirus (CMV) viremia. Symptoms resolved on prednisone and colchicine. A week later, he had an uneventful second COVID-19 vaccine. He went on to have 3 recurrences of pericarditis starting two months after his first. One was within 48 hours of his COVID-19 booster. He is on long term prednisone. Case 2: 66-year-old male with non-Hodgkin’s lymphoma in remission. He developed chest pain a day after his 2nd dose of Pfizer-BioNTech COVID-19 vaccine. Admitted 4 days later with pericardial effusion and managed medically. Readmitted a week later with fever and chest pain. Echocardiogram now showed cardiac tamponade. Pericardiocentesis removed 400 ml of exudative fluid with 1,191 nucleated cells/mL. Cultures for bacteria, fungi, and mycobacteria were negative. Cytology didn't show malignancy. Serologies for CMV, EBV and parvovirus represented past infection. He was discharged with a pericardial drain, colchicine, and NSAIDs. He was later readmitted with fevers. Echocardiogram only showed small pericardial effusion, which did not require drainage. Figure 1Circumferential pericardial effusion seen on trans-thoracic echocardiography from patient in case 1. Conclusion Given the proximity to COVID-19 vaccination and lack of alternative explanations, we believe that tamponade was a direct result of post-vaccine inflammatory pericarditis. Neither patient had a prior history of pericardial effusion. Both tested negative for SARS-CoV-2 by nasopharyngeal swab excluding active infection. Healthcare providers should consider the possibility of pericardial effusion and tamponade in patients with chest pain, shortness of breath, or hypotension following COVID-19 vaccination. Disclosures All Authors: No reported disclosures.