This article provides the first proteomic analysis of platelets from COVID-19 patients. Our dataset shows that platelets are reprogrammed during severe COVID-19 and respond with the activation of type I interferon and cell death pathways, indicating platelet participation in the antiviral response. Additionally, identification of proteins involved in translation, mainly in non-surviving, and complete sequencing of SARS-CoV-2 genome call attention to platelets as viral repositories and markers poor prognosis in COVID-19.