Background: Optimal management of Enterococcus faecium bloodstream infection (BSI) is not fully understood. Methods: Multicentre retrospective observational study of all consecutive adult (≥18 years old) patients with E. faecium BSI, between January 2016 and December 2023, at two tertiary teaching hospitals in northern Italy. Patients who died within 48 h from BSI onset were excluded. Primary and secondary endpoints were 30 day mortality and persistent E. faecium BSI, respectively. Cox regression and logistic binary analyses were used. Results: Overall, 391 patients were enrolled: median age was 72 (IQR 61–81) years, 225 were male (57.5%), median Charlson comorbidity index (CCI) was 6 (IQR 4–8) and 94 had immunosuppression (24.0%). BSIs were primary, secondary and device-related in 25.1%, 36.2% and 38.7%, respectively. Vancomycin resistance was found in 30.3%. The appropriate empirical therapy rate was given for 29.1%. All-cause 30 day mortality was 34.3% and the rate of persistent BSI was 18.8%. Variables independently associated with 30 day mortality were immunosuppression (HR 1.638, 95% CI 1.022–2.625, P = 0.040), SOFA (HR 1.205, 95% CI 1.144–1.268, P < 0.001), primary BSI (HR 1.839, 95% CI 1.221–2.770, P = 0.004), source control (HR 0.534, 95% CI 0.260–0.972, P = 0.042) and the performance of follow-up blood cultures (HR 0.403, 95% CI 0.280–0.972, P < 0.001). Factors independently associated with persistent E. faecium BSI were: CCI (OR 1.157, 95% CI 1.030–1.300, P = 0.014), source control not performed (OR 3.275, 95% CI 1.113–9.635, P = 0.031) and teicoplanin (OR 2.023, 95% CI 1.018–4.018, P = 0.044). Conclusions: Among modifiable clinical factors in patients with E. faecium BSI, source control and the execution of follow-up blood cultures demonstrated a protective effect on 30 day mortality. Teicoplanin as targeted antibiotic treatment was independently associated with persistent BSI.