question: BACKGROUND: Early and accurate identification of septic patients at high risk for ICU mortality can help clinicians make optimal clinical decisions and improve the patients’ outcomes. This study aimed to develop and validate (internally and externally) a mortality prediction score for sepsis following admission in the ICU. METHODS: We extracted data retrospectively regarding adult septic patients from one teaching hospital in Wenzhou, China and a large multi-center critical care database from the USA. Demographic data, vital signs, laboratory values, comorbidities, and clinical outcomes were collected. The primary outcome was ICU mortality. Through multivariable logistic regression, a mortality prediction score for sepsis was developed and validated. RESULTS: Four thousand two hundred and thirty six patients in the development cohort and 8359 patients in three validation cohorts. The Prediction of Sepsis Mortality in ICU (POSMI) score included age ≥ 50 years, temperature < 37 °C, Respiratory rate > 35 breaths/min, MAP ≤ 50 mmHg, SpO2 < 90%, albumin ≤ 2 g/dL, bilirubin ≥ 0.8 mg/dL, lactate ≥ 4.2 mmol/L, BUN ≥ 21 mg/dL, mechanical ventilation, hepatic failure and metastatic cancer. In addition, the area under the receiver operating characteristic curve (AUC) for the development cohort was 0.831 (95% CI, 0.813–0.850) while the AUCs ranged from 0.798 to 0.829 in the three validation cohorts. Moreover, the POSMI score had a higher AUC than both the SOFA and APACHE IV scores. Notably, the Hosmer–Lemeshow (H–L) goodness-of-fit test results and calibration curves suggested good calibration in the development and validation cohorts. Additionally, the POSMI score still exhibited excellent discrimination and calibration following sensitivity analysis. With regard to clinical usefulness, the decision curve analysis (DCA) of POSMI showed a higher net benefit than SOFA and APACHE IV in the development cohort. CONCLUSION: POSMI was validated to be an effective tool for predicting mortality in ICU patients with sepsis. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12967-021-03005-y.