Objectives: SARS-CoV-2 Sepsis has increased the use of Empirical Antibiotic Therapy to reduce mortality. However, there is insufficient evidence of this fact. Therefore, the present study will determine whether using empirical antibiotic therapy is associated with 28-day mortality in patients with SARS-CoV-2 Sepsis.Methods: Prospective cohort study, 102 patients were diagnosed with SARS-CoV-2 Sepsis, 52 received Empirical Antibiotic Therapy (AET) guided by the clinical presentation, and 50 did not receive empirical antibiotic therapy (NAET) between February and September 2021.Results: There were significant differences in favour of patients who received empirical antibiotic therapy such as procalcitonin (p=0.03), leukocytes (p=0.025), albumin (p=0.01), and SOFA scale (p=0.022). In both groups, PaFiO2 was associated with mortality (NAET p=0.013 and AET p=0.01), and the days of hospitalisation only in the group that received antibiotics were associated with mortality (p=0.001). Kaplan Meier's survival analysis determined that empirical antibiotic therapy alone is not a significant variable for mortality (p=0.89); however, multivariable COX regression analysis obtained that the use of empirical antibiotic therapy (HR 1.9 95% CI 1.02-3.91), PaO2/FiO2 (0.99 95% CI 0.98-1.00), ventilator-free days (HR 0.89 95% CI 0.84-0.94) and age (HR 1.03 95% CI 1.003-1.051) are predictors of mortality.Conclusions: We conclude that using empirical antibiotic therapy as the only independent variable is not associated with 28-day mortality in the study patients. The variables that explain 28-day significant mortality in patients with SARS-CoV-2 Sepsis were the use of the empirical antibiotic therapy, the PaO2/FiO2 reduction, the reduction in ventilator-free days, and the increased age.