Molecular hydrogen (H2) is a powerful antioxidant and anti-apoptotic agent. H2 has been studied in a number of clinical studies in the recent years.The aim of this research was to investigate the efficacy and safety of H2 inhalation therapy in patients with hypoxemic and hypercapnic respiratory failure (RF) against exacerbation of chronic obstructive pulmonary disease (COPD) in the post-COVID (Corona Virus Disease 2019) period.Methods. The randomized prospective parallel comparative study included patients (n = 60: 40 men aged 71.2 ± 1.8 years, 20 women aged 70.9 ± 2.8 years) with a post-COVID-19 exacerbation of COPD complicated by hypoxemic/hypercapnic RF. The patients were divided into 2 groups: group 1 (main) (n = 30: 18 men, 12 women), group 2 (control) (n = 30: 18 men, 12 women). To maintain arterial blood saturation ≥ 90 %, patients in both groups received respiratory support (non-invasive ventilation) using the Prisma 25ST device (Lowenstein Medical, Germany) in the BiPAP S/T mode (BiLevel Positive Airway Pressure Spontaneous/Time spontaneous/forced mode 20–24/4–6 cm H2O and O2, respectively; the fractional oxygen concentration in the inhaled gas mixture was ≥ 24%). In addition to standard treatment, patients in the main group received additional H2 therapy (Suisonia device, Japan) through a nasal cannula for 90 minutes daily for 14 days.Results. In patients of the main group, a decrease in the stiffness index was detected from 14.6 ± 1.2 to 6.2 ± 0.6 m/s, and the arterial blood lactate level – from 2.84 ± 0.1 to 0.02 ± 0.1 mmol/l (p < 0.001), the calculated shunt fraction Qs/Qt (venous admixture) – from 27.21 ± 3.4 to 7.14 ± 1.23 (p < 0.01) and an increase in the following parameters: reflection index – from 42.2 ± 2.0 to 66.2 ± 4.9% (p < 0.05), virus-specific IgG level – from 134 ± 125 to 669 ± 164 (p < 0. 05), blood flow velocity in arterioles – from 473 ± 108 to 868 ± 64 μm/s (p < 0.05), blood flow velocity in venules – from 299 ± 56 to 862 ± 69 μm/s (p < 0.05), the 6-minute walk distance – from 57.1 ± 4.4 to 328.9 ± 33.7 m (p < 0.05).Conclusion. H2 inhalations were safe and increased the therapeutic effect when added to standard therapy for patients with hypoxemic and hypercapnic RF during exacerbation of COPD in the post-COVID period.