PNX was described as an uncommon complication in COVID-19 patients but clinical risk predictors and the potential role in patient's outcome are still unclear. We assessed prevalence, risk predictors and mortality of PNX in hospitalized COVID- 19 with severe respiratory failure performing a retrospective observational analysis of 184 patients admitted to our COVID-19 Respiratory Unit in Vercelli from October 2020 to March 2021. We compared patients with and without PNX reporting prevalence, clinical and radiological features, comorbidities, and outcomes. Prevalence of PNX was 8.1% and mortality was >86% (13/15) significantly higher than in patients without PNX (56/169) (P < 0.001). PNX was more likely to occur in patients with a history of cognitive decline (HR: 31.18) who received non-invasive ventilation (NIV) (p < 0.0071) and with low P/F ratio (HR: 0.99, p = 0.004). Blood chemistry in the PNX subgroup compared to patients without PNX showed a significant increase in LDH (420 U/L vs 345 U/L, respectively p = 0.003), ferritin (1111 mg/dl vs 660 mg/dl, respectively p = 0.006) and decreased lymphocytes (HR: 4.440, p = 0.004). PNX may be associated with a worse prognosis in terms of mortality in COVID patients. Possible mechanisms may include the hyperinflammatory status associated with critical illness, the use of NIV, the severity of respiratory failure and cognitive impairment. We suggest, in selected patients showing low P/F ratio, cognitive impairment and metabolic cytokine storm, an early treatment of systemic inflammation in association with high-flow oxygen therapy as a safer alternative to NIV in order to avoid fatalities connected with PNX.