OBJECTIVE To compare the effects of conservative oxygen therapy and conventional oxygen therapy on the efficacy and prognosis of mechanical ventilation support in patients with severe pneumonia. METHODS A prospective randomized controlled study were conducted, 110 patients with severe pneumonia requiring mechanical ventilation in intensive care unit (ICU) of Hefei First People's Hospital from May 2019 to May 2021 were selected and divided into conventional oxygen therapy group (51 cases) and conservative oxygen therapy group (55 cases) according to random number table method. Patients in both groups were treated with invasive to non-invasive sequential mechanical ventilation strategy, and the target of oxygen therapy in the conventional oxygen therapy group was set as the arterial partial pressure of oxygen (PaO2) > 150 mmHg (1 mmHg = 0.133 kPa) or pulse oxygen saturation (SpO2) > 0.96. In the conservative oxygen therapy group, PaO2 was set at 70-100 mmHg or SpO2 at 0.90-0.92. The changes of blood gas analysis, mechanical ventilation time, ICU stay time, ICU mortality, new organ dysfunction and infection more than 48 hours after admission were observed in two groups before and after treatment. Kaplan-Meier method was used to analyze the difference in cumulative survival rate between the two groups. RESULTS After treatment, pH value, PaO2 and oxygenation index (PaO2/FiO2) in both groups were significantly higher than before treatment, and arterial partial pressure of carbon dioxide (PaCO2) was significantly lower than before treatment. pH value in the conservative oxygen therapy group was significantly higher than that in the conventional oxygen therapy group (7.4±0.1 vs. 7.3±0.3). PaO2, PaCO2 and PaO2/FiO2 were significantly lower than those in conventional oxygen therapy group [PaO2 (mmHg): 68.9±4.7 vs. 75.2±6.0, PaCO2 (mmHg): 42.1±5.6 vs. 50.5±7.5, PaO2/FiO2 (mmHg): 329±126 vs. 365±108, all P < 0.05]. The mechanical ventilation time in the conservative oxygen therapy group was significantly longer than that in the conventional oxygen therapy group (days: 19.7±3.5 vs. 13.9±4.5, P < 0.05), but there was no significant difference in ICU hospitalization time between the conservative oxygen therapy group and the conventional oxygen therapy group (days: 26.5±5.0 vs. 25.5±4.6, P > 0.05). Compared with the conventional oxygen therapy group, the ICU mortality, the incidence of nosocomial bloodstream infection, and the incidence of liver insufficiency, shock, and ICU acquired weakness (ICUAW) were decreased significantly in the conservative oxygen therapy group [ICU mortality: 27.3% (15/55) vs. 45.1% (23/51), liver insufficiency: 1.8% (1/55) vs. 7.8% (4/51), shock: 3.6% (2/55) vs. 9.8% (5/51), ICUAW: 5.5% (3/55) vs. 11.8% (6/51), the incidence of new bloodstream infection: 5.5% (3/55) vs. 11.8% (6/51), all P < 0.05]. Kaplan-Meier analysis showed that the cumulative survival rate of the conservative oxygen therapy group was significantly higher than that of the conventional oxygen therapy group (72.7% vs. 54.9%; Log-Rank test: χ2 = 4.244, P = 0.039). CONCLUSIONS Conservative oxygen therapy can reduce ICU mortality, the incidence of shock, liver insufficiency, ICUAW, and bloodstream infection in patients with severe pneumonia, but prolong mechanical ventilation time.