Introduction: In this single center retrospective cohort study, 784 patients with sepsis were enrolled and followed up for at least 30 days. The selected endpoint was an all-cause mortality event., Method: The relationship between MPV-CV + NEU%-CV and all-cause mortality (in-hospital and 30-day) was analyzed by categorizing the patients into four groups according to MPV-CV and NEU%-CV values. For in-hospital mortality, a significantly higher risk of mortality was observed in patients with an MPV-CV ≥ 15.00% + NEU%-CV ≥ 16.00% than in patients of the other groups (P < 0.001). After adjustment for age, sex, body mass index (BMI), infection site, Acute Physiology and Chronic Health Evaluation (APACHE) II score, Sequential Organ Failure Assessment (SOFA) score, use of vasoactive drugs, mechanical ventilation and renal replacement therapy (RRT), hematocrit, albumin, procalcitonin (PCT), and lactate, logistic regression analysis revealed that an MPV-CV ≥ 15.00% + NEU%-CV ≥ 16.00% was an independent predictive factor for in-hospital mortality [adjusted model: odds ratio (OR) = 4.48, 95% CI = 2.92-6.88, P = 0.001]., Results: After adjustment for age, sex, BMI, infection site, APACHE II score, SOFA score, hematocrit, albumin, PCT, lactate, and the use of vasoactive drugs, mechanical ventilation, and RRT, Cox proportional-hazards regression model revealed that an MPV-CV ≥ 15.00% + NEU%-CV ≥ 16.00% was an independent predictive factor for 30-day mortality [adjusted model 1: hazard ratio (HR) = 7.69, 95% CI = 4.15-14.24, P < 0.001; adjusted model 2: HR = 4.07, 95% CI = 2.50-6.62, P < 0.001]., Conclusion: The combination of MPV-CV and NEU%-CV provides a good prognostic value and is a strong independent predictor of short-term clinical outcomes in patients with sepsis. An MPV-CV ≥ 15.00% + NEU%-CV ≥ 16.00% is significantly associated with adverse short-term clinical outcomes.Trial registration number is XJTU2AF2016LSY-04, the registration date is December 2018.