Introduction: Sepsis is a public health problem due to its high prevalence and mortality. Mean platelet volume (MPV), a biomarker reported in routine blood counts, has been investigated and shows promise for determining fatal outcomes in septic patients. Objective: Evaluate whether the mean platelet volume (MPV) and mean platelet volume-to-platelet count (MPV/P) ratio are predictors of clinical severity and mortality in patients with sepsis. Methods: A prospective population cohort of 163 patients aged 18–97 years was recruited at the Intensive Care Unit of Pablo Arturo Hospital, Quito, Ecuador from 2017–2019 and followed up for 28 days. Patients were diagnosed with sepsis based on SEPSIS-3 septic shock criteria; in which the MPV and the MPV/P ratio were measured on days 1, 2, and 3. Sequential organ failure assessment (SOFA) score and presence of septic shock assessed clinical severity. Mortality on day 28 was considered the fatal outcome. Results The average age of the patients was 61,15 years (SD 20,94) and female sex was predominant. MPV cutoff points at days 1, 2 and 3 were >9,45fL, >8,95fL and >8, 85fL; and (MPV/P) ratio >8, 18, >4, 12 y >3, 95, respectively. MPV at days 2 (9,85fL) and 3 (8,55fL) and (MPV/ P) ratio at days 1 (4,42), 2 (4,21), and 3 (8,55), were predictors of clinical severity assessed by septic shock, which reached significance in the ROC curves. MPV and (MPV/P) ratio were also predictors of clinical severity determined by SOFA at days 1, 2, and 3, where higher values were observed in non-survivors reaching significance in all categories. MPV and MPV/P ratio at days 1, 2 and 3 were independent predictor factors of mortality using Cox proportional hazards model (HR 2,31; 95% CI 1,36–3,94), (HR 2,11; 95% CI 1,17–3,82), (HR 2,13; 95% CI 1,07–4,21) and (HR 2,38; 95% CI 1,38–4,12), (HR 2,15; 95% CI 1,14–4,06), (HR 4,43; 95% CI, 1,72–11,37) respectively. Conclusions: MPV and the MPV/P ratio are predictors of clinical severity and mortality in sepsis. The MPV and its coefficient are indicators of the biological behavior of platelets in sepsis. They should be considered as a cost-effective and rapidly available tool that guides the treatment.