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Background: There is no effective therapy for the severe acute respiratory syndrome by coronavirus 2 (SARS-CoV2) responsible for the Coronavirus disease 2019 (Covid-19). To date, dexamethasone has shown a decrease in mortality in patients who require oxygen, especially those with invasive mechanical ventilation. However, it is unknown if another corticosteroid can be used, the optimal dose and its duration, to achieve a better clinical outcome. The objective of the study was to compare the differences in clinical outcome and laboratory results in hospitalized patients with severe SARS-CoV2 Pneumonia treated with dexamethasone at 6 mg doses versus patients treated with high-dose methylprednisolone. Materials and methods: Ambispective cohort study with survival analysis of 216 patients diagnosed with severe Covid-19 pneumonia confirmed by polymerase chain reaction for SARS-CoV2 by Berlin protocol, who were hospitalized in a high-complexity clinic in Medellín, Colombia. The patients should also have supplementary oxygen and radiological confirmation of Pneumonia by chest tomography. Sample size was not calculated since the total population that met the inclusion criteria was evaluated. 111 patients were treated with the institutional protocol with intravenous dexamethasone 6 mg QD for seven to 10 days if they required oxygen. Since September 15, 2020, the hospitalization protocol of the clinic was modified by the Infectious Diseases and Pulmonology service, recommending a high dose of methylprednisolone of 250 to 500 mg every day for three days with a subsequent change to oral prednisone 50 mg every day for 14 days. The protocol was not applied in the intensive care unit, where dexamethasone continued to be administered. The clinical outcome and differences in laboratory results of the patients who received dexamethasone vs. the prospective cohort that received methylprednisolone from September 15 to October 31, 2020, were evaluated. Follow-up was carried out by outpatient consultation one month after discharge or by telephone, inquiring about readmission or living-dead status. Results: 216 patients had Covid-19 pneumonia documented by ground-glass imaging and alveolar pressure / inspired oxygen fraction (PaFi) less than 300. 111 patients received dexamethasone (DXM) and 105 received methylprednisolone (MTP). Patients in the DXM group evolved to severe ARDS in a higher proportion (26.1% vs 17.1% than the MTP group). Upon completion 4 days of treatment with parenteral corticosteroid, laboratory markers of severity decreased significantly in the group that received MTP, CRP 2.85 (2.3–3.8) vs 7.2 (5.4–9.8), (p-value < 0.0001), D-dimer 691 (612–847) vs 1083 (740–1565) (p-value = 0.04) and DHL 273 (244–289) vs 355 (270.6–422) (p-value = 0.01). After starting the corticosteroid, transfer to the intensive care unit (4.8% vs. 14.4%) and mortality (9,5% vs. 17.1%) was lower in the group that received MTP. Recovery time was shorter in patients treated with MTP, three days (3–4) vs. DXM 6 days (5–8) (p-value < 0.0001). At 30-day follow-up, 88 (92.6%) were alive in MTP vs 58 (63.1%) of those who received dexamethasone. Conclusions: In this study, the treatment of severe Covid-19 Pneumonia with high-dose methylprednisolone for three days followed by oral prednisone for 14 days, compared with 6 mg dexamethasone for 7 to 10 days, statistically significantly decreased the recovery time, the need for transfer to intensive care and the severity markers C-reactive protein (CRP), D-dimer and LDH. Randomized controlled studies with methylprednisolone are required to corroborate its effect, and studies in a population hospitalized in intensive care wards. [ABSTRACT FROM AUTHOR]