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Ruxolitinib is a JAK1\/JAK2 inhibitor with potent anti-inflammatory properties. We report on a prospective, observational study in 34 patients with COVID-19 who received ruxolitinib on a compassionate-use protocol. Patients had severe pulmonary disease defined by pulmonary infiltrates on imaging and an oxygen saturation\u2009\u2264\u200993% in air and\/or PaO2\/FiO2 ratio\u2009\u2264\u2009300\u2009mmHg. Median age was 80.5 years, and 85.3% had\u2009\u2265\u20092 comorbidities. Median exposure time to ruxolitinib was 13 days, median dose intensity was 20 mg\/day. Overall survival by day 28 was 94.1%. Cumulative incidence of clinical improvement of \u22652 points in the ordinal scale was 82.4% (95% confidence interval, 71\u201393). Clinical improvement was not affected by low-flow versus high-flow oxygen support but was less frequent in patients with PaO2\/FiO2\u2009&lt;\u2009200\u2009mmHg. The most frequent adverse events were anemia, urinary tract infections, and thrombocytopenia. Improvement of inflammatory cytokine profile and activated lymphocyte subsets was observed at day 14. In this prospective cohort of aged and high-risk comorbidity patients with severe COVID-19, compassionate-use ruxolitinib was safe and was associated with improvement of pulmonary function and discharge home in 85.3%. 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