Background Ivermectin was shown to inhibit SARS-CoV-2 replication in-vitro, which has led to off-label use, but clinical efficacy has not been previously described. Research Question Does ivermectin benefit hospitalized COVID-19 patients? Study Design and Methods: Charts of consecutive patients hospitalized at four Broward Health hospitals in Florida with confirmed COVID-19 between March 15 through May 11, 2020 treated with or without ivermectin were reviewed. Hospital ivermectin dosing guidelines were provided but treatment decisions were per treating physician’s discretion. The primary outcome was all-cause in-hospital mortality. Secondary outcomes included mortality in patients with severe pulmonary involvement, extubation rates for mechanically ventilated patients, and length of stay. Severe pulmonary involvement was defined as need for FiO 2 ≥50%, noninvasive ventilation, or invasive ventilation at study entry. Logistic regression and propensity score matching were used to adjust for confounders. Results 280 patients, 173 treated with ivermectin and 107 without ivermectin, were reviewed. Most patients in both groups also received hydroxychloroquine and/or azithromycin. Univariate analysis showed lower mortality in the ivermectin group (15.0% versus 25.2%, OR 0.52, CI 0.29-0.96, P=0.03). Mortality was also lower among ivermectin-treated patients with severe pulmonary involvement (38.8% vs 80.7%, OR 0.15, CI 0.05-0.47, p=0.001). There were no significant differences in extubation rates (36.1% vs 15.4%, OR 3.11 (0.88-11.00), p=0.07) or length of stay. After multivariate adjustment for confounders and mortality risks, the mortality difference remained significant (OR 0.27, CI 0.09-0.80, p=0.03). 196 patients were included in the propensity-matched cohort. Mortality was significantly lower in the ivermectin group (13.3% vs 24.5%, OR 0.47, CI 0.22-0.99, p<0.05); an 11.2% (CI 0.38%-22.1%) absolute risk reduction, with a number needed to treat of 8.9 (CI 4.5-263). Interpretation Ivermectin treatment was associated with lower mortality during treatment of COVID-19, especially in patients with severe pulmonary involvement. Randomized controlled trials are needed to confirm these findings.