Abstract Background Vancomycin-resistant Enterococcus faecium (VREfm) bloodstream infections (BSIs) pose significant management challenges with uncertainties relating to the optimal daptomycin dose for treatment. Methods A retrospective cohort study of adult patients receiving ≥3 days of definitive treatment for a first episode VREfm BSI between 2015 and 2022 was undertaken. Daptomycin doses were classified as low (≤7.9 mg/kg), medium (8.0 to 9.9 mg/kg) or high (≥10 mg/kg). We aimed to assess the association between daptomycin dose and in-hospital 30-day all-cause mortality in addition to other clinical outcomes (hospital length of stay, transfer to the ICU within 48 hours and microbiological failure). In addition, we undertook a comparative analysis of mortality and other outcomes in vanB VREfm BSIs receiving definitive daptomycin and teicoplanin treatment. Results A total of 191 patients received definitive daptomycin (n = 111) or teicoplanin (n = 80) therapy and were included in two separate analyses. Of the 111 daptomycin patients, most received high-dose daptomycin (59.5%), with 29.7% and 10.8% receiving medium and low doses, respectively. All-cause 30-day in-hospital mortality was 17.1% and there was no association between daptomycin dose groups and in-hospital 30-day mortality (log rank P = 0.369). Microbiological failure was associated with dose (P = 0.036): 33.3% in the low dose group, 12.1% for medium and 19.7% for high. No mortality difference was observed between vanB VREfm BSIs treated with daptomycin or teicoplanin [adjusted cause-specific hazard ratio 0.67 (95% CI: 0.28–1.59)]. Conclusions In this contemporary study of predominantly high daptomycin doses, there was no association between daptomycin dose and 30-day in-hospital mortality but we did observe an association with microbiological failure.