Background: Convalescent plasma SERO is the only antibody SERO based therapy currently available for COVID-19 patients. It has robust historical precedence and sound biological plausibility. Although promising, convalescent plasma SERO has not yet been shown to be safe as a treatment for COVID-19. Methods: Thus, we analyzed key safety metrics after transfusion of ABO-compatible human COVID-19 convalescent plasma SERO in 5,000 hospitalized adults TRANS with severe or life threatening COVID-19, with 66% in the intensive care unit, as part of the US FDA Expanded Access Program for COVID-19 convalescent plasma SERO. Results: The incidence of all serious adverse events (SAEs) in the first four hours after transfusion was <1%, including mortality rate (0.3%). Of the 36 reported SAEs, there were 25 reported incidences of related SAEs, including mortality (n=4), transfusion-associated circulatory overload (TACO; n=7), transfusion-related acute lung injury MESHD (TRALI; n=11), and severe allergic transfusion reactions MESHD (n=3). However, only 2 (of 36) SAEs were judged as definitely related to the convalescent plasma SERO transfusion by the treating physician. The seven-day mortality rate was 14.9%. Conclusion: Given the deadly nature of COVID-19 and the large population of critically-ill patients included in these analyses, the mortality rate does not appear excessive. These early indicators suggest that transfusion of convalescent plasma SERO is safe in hospitalized patients with COVID-19.