Objective To explore the predictive value of changes in mean platelet volume (MPV) for prognosis of septic shock patients in early stage. Methods A retrospective cohort study was conducted on the 366 patients (over 18 years old) who were diagnosed by Sepsis 3.0 diagnostic criteria admitted to our department from July 2018 to June 2020. They were divided into survival group and death group according to 28-day survival conditions. General data, clinical baseline data, and MPV, platelet count (PLT), platelet distribution width (PDW), large platelet ratio (P-LCR) and plateletcrit (PCT) in 5 d after diagnosis were collected and compared between the two groups. SPSS statistics 25.0 was used to perform the statistical analysis. Independent sample t test was used to analyze the measurement data of continuous normal distribution which were expressed as mean±standard deviation (±s); the data of non-normal distribution were expressed as median and quartile [M (Q₁, Q₃)] and analyzed with nonparametric test; enumeration data were expressed as percentage, and inter-group comparison was carried out with Chi-square test or Fisher exact probability test. Results For the 202 enrolled septic shock patients, 100 survived and 102 died. The patients in the death group were older, more likely to be complicated with chronic renal diseases, and with higher score of acute physiology and chronic health evaluation (APACHE) Ⅱ and higher lactic acid level, but worse coagulation function and liver and kidney function, when compared with those in the survival group (all P<0.05). For the platelet parameters, MPV, PDW and P-LCR were significantly higher, while PLT and PCT were obviously lower in the death group than the survival group (all P<0.05). Receiver operating characteristic (ROC) curve analysis showed the area under ROC curve of MPV (AUC=0.92) was the largest. Multivariate logistic regression analysis indicated that MPV (OR=4.78,95%CI 2.75-8.31), lactate (OR=2.20,95%CI 1.23-3.93), APACHE Ⅱ score (OR=1.87,95%CI 1.41-2.48), and PCT (OR=0.88,95%CI 0.80-0.97) were independent risk factors for 28-day mortality. Based on the results of multivariate regression, a multi-parameter model was established, and showed a good predictive value for the 28-day prognosis of septic shock (AUC=0.98). Conclusion Early continuous rise of MPV is an important independent risk factor for 28-day mortality, and shows higher predictive value for prognosis in septic shock patients.