ABSTRACT Background There is no clear pharmacokinetic and pharmacodynamic (PK/PD) target during vancomycin‐susceptible Enterococcus faecium bacteremia (EFB). Objectives To investigate whether in‐hospital mortality was associated with susceptibility to amoxicillin or vancomycin minimum inhibitory concentration (MIC) of the strain and with area under the curve over 24 h (AUC) and AUC/MIC during EFBs. Methods All E. faecium strains isolated from blood cultures performed between January 1, 2017, and December 31, 2022, were included, and clinicobiological data were retrospectively extracted from corresponding medical records. The Vancomycin MICs were estimated using the VITEK 2 automated system. AUC was calculated among patients who received vancomycin during their first episode of EFB with available data. Results Two hundred fifteen E. faecium strains not susceptible to amoxicillin had been isolated in 207 patients (125 male, median age 69 [1–98] years) with biliary and digestive tract diseases, hematologic malignancies, or COVID‐19 in 124 (59.9%), 35 (16.9%), and 17 (8.2%) cases, respectively. The median vancomycin MIC was 0.5 [0.5–2] mg/L, and 67 patients (32.3%) died during the hospitalization. In‐hospital mortality was not associated with susceptibility to amoxicillin ( p = 0.14) or vancomycin MIC ( p = 0.07) of the strain. Neither mean AUC (592.7 versus 521.7mgh/L) nor mean AUC/MIC ratio (1066.5 versus 1000.5) was associated with in‐hospital mortality ( p = 0.17 and p = 0.54, respectively). Conclusions Besides amoxicillin susceptibility and vancomycin MIC of the strain, there was no significant association between in‐hospital mortality and vancomycin AUC or AUC/MIC. Retrospective observational studies focusing on in‐hospital mortality among patients with severe comorbidities may not be adequate for the determination of the PK/PD target of vancomycin.