Background: Although convalescent plasma has historically yielded significant benefits in the treatment of infectious diseases, numerous clinical trials have not shown a consistent benefit in treating either moderately or severely ill COVID-19 patients with plasma from convalescent patients. We previously reported increased levels of antiphospholipid antibodies (aPL) in acutely ill COVID patients, with high aPL titers correlating with more neutrophil extracellular traps (NETs) and poorer patient outcomes. We hypothesized that persistence of potentially deleterious autoantibodies in previously hospitalized, convalescent plasma donors may activate immune cells and add context for the lack of clinical efficacy in COVID. Methods: 116 samples of convalescent plasma from donors previously hospitalized with COVID were obtained from Vitalant. Antibody titers (IgG, IgM, IgA) of anti-2-glycoprotein 1 (a2GP1) and anti-cardiolipin (aCL) and anti-phosphatidylserine/prothrombin (IgG, IgM) were quantified. NET formation by healthy human neutrophils treated with convalescent plasma was evaluated in vitro. Results: High aPL titers >40 U/mL) were observed in 10/116 (8.6%) convalescent samples, and 6/10 were positive for either IgG or IgM aCL. The aPL positivity rate exceeded the expected background population rate of ~3%. Six of 116 convalescent samples increased NET-associated MPO activity in purified, primary neutrophils from healthy donors compared with control plasma (mean increase of 23% +/- 11, p<0.01), where only 2 of these were aPL-positive samples. Conclusion: aPL were elevated in a larger proportion of surveyed convalescent plasma samples than reported in the healthy population. aPL positivity did not correlate with purified neutrophil activation, suggesting aPL in donor plasma does not have a direct, activating effect on healthy neutrophils. Considering the complex interactions among circulating blood cells, ongoing experiments are examining the impact of convalescent plasma on platelet and endothelial cell function to further elucidate potential autoantibody-mediated vascular perturbations. The results of these studies will be important in informing the vascular implications and safety of convalescent plasma in COVID.