Background Ivermectin was shown to inhibit severe acute respiratory syndrome coronavirus 2 replication in vitro, which has led to off-label use, but clinical efficacy has not been described previously. Research Question Does ivermectin benefit hospitalized coronavirus disease 2019 (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 and May 11, 2020, treated with or without ivermectin were reviewed. Hospital ivermectin dosing guidelines were provided, but treatment decisions were at the 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 F io 2 ≥ 50%, noninvasive ventilation, or invasive ventilation at study entry. Logistic regression and propensity score matching were used to adjust for confounders. Results Two hundred eighty patients, 173 treated with ivermectin and 107 without ivermectin, were reviewed. Most patients in both groups also received hydroxychloroquine, azithromycin, or both. Univariate analysis showed lower mortality in the ivermectin group (15.0% vs 25.2%; OR, 0.52; 95% CI, 0.29-0.96; P = .03). Mortality also was lower among ivermectin-treated patients with severe pulmonary involvement (38.8% vs 80.7%; OR, 0.15; 95% CI, 0.05-0.47; P = .001). No significant differences were found in extubation rates (36.1% vs 15.4%; OR, 3.11; 95% CI, 0.88-11.00; P = .07) or length of stay. After multivariate adjustment for confounders and mortality risks, the mortality difference remained significant (OR, 0.27; 95% CI, 0.09-0.80; P = .03). One hundred ninety-six patients were included in the propensity-matched cohort. Mortality was significantly lower in the ivermectin group (13.3% vs 24.5%; OR, 0.47; 95% CI, 0.22-0.99; P < .05), an 11.2% (95% CI, 0.38%-22.1%) absolute risk reduction, with a number needed to treat of 8.9 (95% 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.