Abstract: Background　Objective　To develop and validate a prediction model for 28-day mortality risk in patients aged≥80 years with E. coli bloodstream infection, providing reference for early identification of high-risk patients in clinical practice. Methods　 A multicenter retrospective cohort study was conducted, enrolling patients aged≥80 years with E. coli bloodstream infection admitted to the First Medical Center, the Second Medical Center, and the Fifth Medical Center of PLA General Hospital from September 2011 to June 2025. Their clinical data were collected. Variables were screened using LASSO regression, followed by multivariate logistic regression modeling to identify factors independently associated with 28-day mortality. Internal validation was performed using the Bootstrap method.Results　 A total of 170 patients were included, with a mean age of 89.45±6.44 years and a 28-day mortality rate of 27.1%. Multivariate analysis showed that advanced age (OR=1.19, 95% CI: 1.10 - 1.28), comorbid dementia (OR=3.97, 95% CI: 1.55 - 10.13), and albumin level (OR=0.86, 95% CI: 0.78 - 0.95) were independently associated with 28-day mortality (P＜0.05). The predictive model demonstrated good discrimination for 28-day mortality (adjusted AUC 0.841). Conclusion　 The 28-day mortality rate among patients aged≥80 years with E. coli bloodstream infection approached one-third. Advanced age, comorbid dementia, and low albumin level are associated with an increased probability of death. These findings may provide references for early risk stratification and individualized treatment in this high-risk population. 　Bloodstream infection is a major risk factor for mortality in very elderly patients aged≥80 years. Escherichia coli (E. coli) is the predominant pathogen; however, prognostic factors for this population, particularly refined assessments integrating multidimensional clinical indicators, remain insufficiently explored.