BACKGROUND: Coronavirus patients demonstrate varying degrees of respiratory insufficiency; many will progress to respiratory failure with a severe version of acute respiratory distress syndrome refractory to traditional supportive strategies. Providers must consider alternative therapies to deter or prevent the cascade of decompensation to fulminant respiratory failure. METHODS: This is a case-series of five COVID-19 positive patients who demonstrated severe hypoxemia, declining respiratory performance, and escalating oxygen requirements. Patients met the following criteria: COVID-19 positivity, worsening respiratory performance, severe hypoxemia (PaO2 </= 80) despite traditional supportive measures, escalating supplemental oxygen requirements, and D-dimer greater than 1.5 mug/mL. All patients received protocol directed thrombolytic therapy with tissue plasminogen activator (tPA). RESULTS: All five patients improved without deleterious effects of thrombolytic therapy. Patient one was on maximum ventilator support, paralytics, and prone positioning without improvement. During tPA administration his PaO2/FIO2 ratio improved from 69 to 127. Ventilator support was weaned immediately on posttreatment day 1, and he was extubated on posttreatment day 12. Our second through fifth patients were not intubated at time of initiation of tPA therapy. These patients each required significant oxygen supplementation trending toward intubation. After tPA therapy, all patients demonstrated a noticeable increase in PaO2 values overtime. Three of these patients avoided intubation due to COVID-19-associated respiratory failure. CONCLUSION: Administration of thrombolytics was followed by overall improvement in patients' oxygen requirements, and in three cases, prevented progression to mechanical ventilation, without deleterious effects. Clinical trials of thrombolytic therapy would further serve to underscore the efficacy and utility of this therapy. LEVEL OF EVIDENCE: Case series of therapeutic effect, Level V.