This non-randomized controlled study aimed to assess the efficacy of tofacitinib in reducing the risk of invasive mechanical ventilation or death in patients with COVID-19. Patients with COVID-19 associated with reduced oxygen saturation, increased C-reactive protein (≥50 mg/L), and/or persisting fever were recruited. Tofacitinib was administered in addition to standard of care therapy. Study outcomes were evaluated separately in the groups of patients with oxygen saturation at rest ≤93% and >93%. Hazard ratios (HR) with 95% confidence intervals (CI) were calculated using Cox regression analysis adjusted for inverse propensity score weighting. Overall, 384 patients with COVID-19 (212 males; median age 60 years) were included in our study and were treated with tofactinib (n=131) or standard of care alone (n=253). The percentages of patients who started mechanical ventilation or died during hospitalization in the tofacitinib and control groups were 12.5% (9/72) vs. 14.1% (26/185) among patients who required respiratory support (HR 0.92, 95% CI 0.33-2.56), and 1.7% (1/59) vs. 4.4% (3/68) in those with normal oxygen saturation (HR 0.83; 95 CI 0.07-9.44). Tofacitinib did not reduce the risk of invasive mechanical ventilation or death in patients with COVID-19, although the analysis of these outcomes favored tofacitinib.