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Data suggest that coronavirus disease 2019 (COVID-19) results in a prothrombotic state leading to arterial and venous thromboses. Vaccination, novel antiviral drugs, and emerging variants have changed the course of the disease in many ways; however, their effects on the incidence of thrombotic events and the efficacy of preventative antithrombotic agents have not been yet evaluated. A systematic search was conducted to identify studies reported on the incidence of thrombotic events based on vaccination status, use of novel antiviral drugs, and emerging viral variants. Similarly, we screened the ongoing/published randomized trials of preventative antithrombotic therapy in any COVID-19 population to assess whether subgroup-specific results were reported based on any of these variants. Upon searching a total of 3,451 records, only one entry fulfilled the inclusion criteria of our systematic review, which was a self-controlled case series on 29,121,633 vaccinated individuals, the incidence rate ratio of thrombotic complication after breakthrough infection was 13.86 (95% confidence interval [CI]: 12.76-15.05) compared with 1.10 (95% CI: 1.02-1.18) during the 28-day postvaccination. In conclusion, although the mortality benefit of mass vaccination and the early promising results of the new antiviral therapies are well known, we were unable to find clinical evidence on whether vaccination, the use of novel antiviral agents, and emerging viral variants have affected the incidence rate of thrombotic events or impacted the efficacy of prophylactic antithrombotic therapy in patients with COVID-19. Analyses from existing trials and large-scale registries can provide interim knowledge and any findings of relevance should be incorporated in the design of future trials., Competing Interests: Disclosure The authors report no conflicts of interest in this work., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)