Abstract: Clinical Drug Investigation (2021) 41:723–732 https://doi.org/10.1007/s40261-021-01061-2 ORIGINAL RESEARCH ARTICLE Acetylsalicylic Acid Compared with Enoxaparin for the Prevention of Thrombosis and Mechanical Ventilation in COVID‑19 Patients: A Retrospective Cohort Study Heba Wagih Abdelwahab1 · Shaker Wagih Shaltout2 · Hazem A. Sayed Ahmed3 · Ahmed Mahmoud Fouad4 · Eric Merrell5 · Jeffrey B. Riley6 · Rasha Salama4 · Ahmed Gharib Abdelrahman3 · Edward Darling6 · Ghada Fadel11 · Mohamed S. A. Elfar7 · Khaled Sabry8 · Jaffer Shah9 · Hossam Amin10 · Gary F. Nieman11 · Adel Mishriky4 · Hani Aiash3,6,11 Accepted: 6 July 2021 / Published online: 30 July 2021 © The Author(s), under exclusive licence to Springer Nature Switzerland AG 2021 Abstract Background and Objective Low-dose acetylsalicylic acid (ASA, aspirin) is a well-known and frequently studied drug for primary and secondary prevention of disease due to its anti-inflammatory and coagulopathic effects. COVID-19 complications are attributed to the role of thrombo-inflammation. Studies regarding the use of low-dose ASA in COVID-19 are limited. For this reason, we propose that the use of low-dose ASA may have protective effects in COVID-19–related thromboembolism and lung injury. This study was conducted to assess the efficacy of low-dose ASA compared with enoxaparin, an anticoagulant, for the prevention of thrombosis and mechanical ventilation. Methods We conducted a retrospective cohort study on COVID-19-confirmed hospitalized patients at the Mansoura University Quarantine Hospital, outpatients, and home-isolated patients from September to December 2020 in Mansoura governorate, Egypt. Binary logistic regression analysis was used to assess the effect of ASA compared with enoxaparin on thromboembolism, and mechanical ventilation needs. Results This study included 225 COVID-19 patients. Use of ASA-only (81–162 mg orally daily) was significantly associated with reduced thromboembolism (OR 0.163, p = 0.020), but both low-dose ASA and enoxaparin, and enoxaparin-only (0.5 mg/kg subcutaneously (SC) daily as prophylactic dose or 1 mg/kg SC every 12 hours as therapeutic dose) were more protective (odds ratio [OR] 0.010, OR 0.071, respectively, p < 0.001). Neither ASA-only nor enoxaparin-only were associated with a reduction in mechanical ventilation needs. Concomitant use of low-dose ASA and enoxaparin was associated with reduced mechanical ventilation (OR 0.032, 95% CI 0.004–0.226, p = 0.001). Conclusions Low-dose ASA-only use may reduce the incidence of COVID-19-associated thromboembolism, but the reduction may be less than that of enoxaparin-only, and both ASA and enoxaparin. Concomitant use of ASA and enoxaparin demonstrates promising results with regard to the reduction of thrombotic events, and mechanical ventilation needs.