question: AIMS: No standard therapy is currently recommended for moderately ill Corona-virus-19 disease (COVID-19) patients. Potential benefit in terms of survival for anticoagulation were found only in this subset of patients. Aim of this study was to evaluate safety and efficacy of add-on antiplatelet therapy with aspirin over prophylactic anticoagulation (PAC) in COVID-19 hospitalized patients and its impact on survival. METHODS AND RESULTS: 7824 consecutive patients with COVID-19 were enrolled in a multicentre-international prospective registry (HOPE-COVID-19). Clinical data and in-hospital complications, including mortality, were recorded. Study population included only patients treated with aspirin and/or PAC. A comparison of clinical outcomes between add-on antiplatelet therapy and PAC and patients treated with PAC only was performed using an adjusted analysis with propensity score (PS) matching. Of 7824 patients, 360 (4.6%) received PAC and aspirin and 2949 (37.6%) PAC only. Propensity-score matching yielded 298 patients from each group. Mean age was 73 ± 11 years, 67% were male, prevalence of hypertension and diabetes was 79% and 33%, respectively, and 7.5 % underwent invasive ventilation. In the propensity score-matched population, cumulative incidence curves of in-hospital mortality were lower in patients treated with PAC and Aspirin vs. PAC only (15% vs. 21%, Log Rank P = 0.01). At multivariable analysis in propensity matched population of COVID-19 patients, including age, sex, hypertension, diabetes, kidney failure and invasive ventilation, aspirin treatment was associated with lower risk of in-hospital mortality (HR: 0.62, CI: 95% 0.42–0.92, P = 0.018). CONCLUSIONS: Add-on anti-platelet therapy with aspirin over PAC in COVID-19 hospitalized patients was associated with lower mortality risk in a propensity score matched population.