Abstract Objectives Bloodstream infections (BSIs) due to vancomycin-resistant Enterococcus spp. (VRE) are considered a predictor of mortality among frail patients. The aim of this study was to evaluate the risk factors associated with 30 day mortality and relapse of infection in enterococcal BSI caused by VRE and to evaluate the impact of antibiotic regimens in targeted therapy. Methods We conducted a retrospective study of consecutive hospitalized patients in six teaching hospitals from August 2016 to August 2022 in Italy. All adult patients with a documented VRE BSI were included. Results We enrolled 517 consecutive hospitalized patients with VRE BSI; of these BSIs 496 (96.5%) were caused by Enterococcus faecium and 26 (5.1%) by Enterococcus faecalis. The most frequently used antibiotics as backbone were linezolid (48.1%) and daptomycin (43.7%). Overall, the 30 day mortality was 32.1%. Upon Cox regression analysis, the risk factor independently associated with 30 day mortality was Charlson comorbidity index >3 points (P < 0.001), whereas a Pitt score <4 points (P = 0.031), surgery for source control of infection (P = 0.016) and time to targeted therapy <24 h (P = 0.006) were associated with survival. After propensity score adjustment, a daptomycin-based regimen (P = 0.003) was associated with 30 day survival. Conclusions VRE BSI is an important cause of mortality in frail/critically ill patients. Our data highlighted the role of daptomycin as backbone agent for the treatment of enterococcal BSI caused by vancomycin-resistant strains.