OBJECTIVE: To analyze the effects of a short course of methyl-prednisolone pulses (MP) during the second week of disease MESHD (week-2) on the clinical course of patients with severe coronavirus disease MESHD 2019 (COVID-19) pneumonia MESHD pneumonia HP. DESIGN: Comparative observational study using data collected from routine care. SETTING: Hospital Universitario Cruces, a tertiary level University hospital at Barakaldo, Bizkaia, Spain. PARTICIPANTS: All patients with COVID-19 pneumonia MESHD pneumonia HP admitted between 1st March and 30th April 2020 to the services of Infectious Diseases MESHD and Internal Medicine. INTERVENTIONS: Treatment with week-2-MP (125-250 mg/d for 3 consecutive days with no subsequent tapering) vs. standard of care. MAIN OUTCOMES MEASURES: Time to death MESHD and time to death MESHD or endotracheal intubation. RESULTS: Two hundred and forty-two patients with confirmed COVID-19 pneumonia MESHD pneumonia HP and elevated inflammatory markers at admission were included in the study. Sixty-one patients (25%) received week-2-MP. Twenty-two patients (9%) died during the study period. Thirty-one patients (12.8%) suffered death MESHD or intubation. The adjusted HR for death MESHD was 0.35 (95%CI 0.11 to 1.06, p= 0.064) for patients in the week-2-MP group. The adjusted HR for death MESHD or intubation week-2-MP was 0.33 (95%CI 0.13 to 0.84, p=0.020) for patients in the week-2-MP group. These differences were seen in the subcohort of patients with a SaO2/FiO2 at day 7 lower than the median of the whole population: HR 0.31, 95% CI 0.08 to 1.12, p=0.073 and HR 0.34, 95%CI 0.12 to 0.94, p=0.038, respectively, but not in patients with higher SaO2/FiO2. Other predictors of the final outcomes were arterial hypertension MESHD hypertension HP, SaO2/FiO2, high-risk CURB65 scores and the use of non-pulse glucocorticoids. Non-pulse glucocorticoids were a predictor of infections MESHD (OR 4.72, 95%CI 1.90 to 11.80, p<0.001), while week-2-MP were not (OR 1.04, 95%CI 0.40 to 2.70, p=0.938). CONCLUSIONS: Week-2-MP are effective in improving the prognosis of patients with COVID-19 pneumonia MESHD pneumonia HP with features of inflammatory activity and respiratory deterioration entering the second week of disease MESHD. The recognition of this high-risk population should prompt early use of MP at this point. REGISTRATION: This study has been registered in the EU PAS Register with the number EUPAS36287.