RATIONALE: Subtle Pulse Electro-biological Recovery Apparatus (SPERA) is an innovative device which delivers digital subliminal pulse stimulation transcranially and modulates the auricular branches of the vagus nerve. The aim of this single centre, interventional study was to assess the efficacy and safety of non-invasive trans-cranial direct current auricular Vagus Nerve Stimulation (aVNS) in patients with SARS-CoV-2 infection. METHODS: Patients hospitalised with moderate-to-severe COVID-19 were enrolled in the study. Inclusion criteria were: RT-PCR confirmed SARS-CoV-2 infection, lung involvement as demonstrated by chest CT scan, elevated inflammatory markers (CRP>46mg/L, ferritin>250ng/mL). SPERA therapy was administered on top of the standard of care treatment and several clinical and paraclinical outcomes were compared between SPERA and matched control group. RESULTS: Thirty-two patients received SPERA therapy, while 50 patients matched for age, sex, comorbidities and severity of disease were included in the control group. We found significant reduction in ICU admission (16% vs. 54%, p<0.001), need for NIV (16% vs. 42%, p=0.006), mechanical ventilation (12.5% vs. 46%, p<0.001) and mortality rate (31% vs. 62%, p=0.003) in SPERA vs. control group. Admission to ICU (HR:2.53, p=0.005), the use of mechanical ventilation (HR:4.25, p<0.01), high IL-6 (>50 pg/l, HR:3.24, p<0.01) and the presence of septic shock (HR=5.53, p<0.001) were among the risk factors for death, but not aVNS (HR=0.41, p=0.02). CONCLUSION: aVNS therapy may be an effective and safe intervention in COVID-19 hospitalised patients, however further research is warranted.