Abstract: Open Forum Infectious Diseases MAJOR ARTICLE Role of Low-Molecular-Weight Heparin in Hospitalized Patients With Severe Acute Respiratory Syndrome Coronavirus 2 Pneumonia: A Prospective Observational Study 1 Infectious Disease Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy, 2Emergency Medicine Unit, Department of Clinical and Experimental Medicine, University Hospital of Pisa, Pisa, Italy, 3Internal Medicine, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy, 4Department of Surgical, Medical and Molecular Pathology and Critical Care Medicine, University of Pisa, Pisa, Italy, 5Anaesthesia and Intensive Care Unit, Ospedali Galliera, Genova, Italy, 6Department of Anesthesia and Critical Care Medicine, Azienda Ospedaliero Universitaria Pisana, Pisa, Italy, 7Department of Emergency Medicine, Azienda Ospedaliera Universitaria Pisana, Pisa, Italy, 8Geriatric Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy, 9Department of Internal Medicine, Azienda Ospedaliera Universitaria Pisana, Pisa, Italy, 10Virology Unit, Department of Laboratory Medicine Pisa University Hospital and Retrovirus Center, Department of Translational Research, University of Pisa, Pisa, Italy, 11Unit of Clinical Pharmacology and Pharmacogenetics, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy, 12Department of Economics and Finance University of Rome “Tor Vergata”, Rome, Italy Background. This study was conducted to evaluate the impact of low-molecular-weight heparin (LMWH) on the outcome of patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia. Methods. This is a prospective observational study including consecutive patients with laboratory-confirmed SARS-CoV-2 pneumonia admitted to the University Hospital of Pisa (March 4–April 30, 2020). Demographic, clinical, and outcome data were collected. The primary endpoint was 30-day mortality. The secondary endpoint was a composite of death or severe acute respiratory distress syndrome (ARDS). Low-molecular-weight heparin, hydroxychloroquine, doxycycline, macrolides, antiretrovirals, remdesivir, baricitinib, tocilizumab, and steroids were evaluated as treatment exposures of interest. First, a Cox regression analysis, in which treatments were introduced as time-dependent variables, was performed to evaluate the association of exposures and outcomes. Then, a time-dependent propensity score (PS) was calculated and a PS matching was performed for each treatment variable. Results. Among 315 patients with SARS-CoV-2 pneumonia, 70 (22.2%) died during hospital stay. The composite endpoint was achieved by 114 (36.2%) patients. Overall, 244 (77.5%) patients received LMWH, 238 (75.5%) received hydroxychloroquine, 201 (63.8%) received proteases inhibitors, 150 (47.6%) received doxycycline, 141 (44.8%) received steroids, 42 (13.3%) received macrolides, 40 (12.7%) received baricitinib, 13 (4.1%) received tocilizumab, and 13 (4.1%) received remdesivir. At multivariate analysis, LMWH was associated with a reduced risk of 30-day mortality (hazard ratio [HR], 0.36; 95% confidence interval [CI], 0.21–0.6; P < .001) and composite endpoint (HR, 0.61; 95% CI, 0.39–0.95; P = .029). The PS-matched cohort of 55 couples confirmed the same results for both primary and secondary endpoint. Conclusions. This study suggests that LMWH might reduce the risk of in-hospital mortality and..