In COVID-19, thromboembolic complications represent one of the most relevant signs associated with mortality. It has been proposed the use of LMWH in therapeutic dosage therefore off-label. Between March and April 2020, sixteen patients with COVID-19 were admitted to our structure for major non-deferrable orthopedic surgery. The first series of patients received prophylactic treatment of 4000 UI/die of LMWH, while the second series of 9 patients were treated with 4000 IU/twice a day. The data collected and published so far indicate that LMWH has a favorable benefit/risk ratio with efficacy in the prophylaxis of thromboembolic phenomena in COVID-19 patients undergoing orthopedic surgery, greater than any adverse events. The reduction of associated disseminated thromboembolic phenomena with the escalated dose of LMWH does not represent the cure for COVID-19 but could favor survival. It will be necessary to collect further data on the off-label use of LMWH in this patient setting to legitimize a request for extension of indication to the regulatory authorities.