Background:Enterococcus faecalisis responsible for a large variety of severe infections. This study is a case series reporting our experience in the treatment ofE. faecalisinvasive infections with ampicillin in combination with ceftobiprole (ABPR). Methods: We retrospectively analyzed all the medical records of patients admitted to the University Hospital of Udine from January to December 2020 with a diagnosis of infective endocarditis or primary or non-primary complicated or uncomplicated bacteremia caused byE. faecalis. Results: Twenty-one patients were included in the final analysis. The clinical success rate was very high, accounting for 81% of patients, and microbiological cure was obtained in 86% of patients. One relapse was recorded in one patient who did not adhere to the partial oral treatment prescribed. Therapeutic drug monitoring (TDM) was always performed for ampicillin and ceftobiprole, and serum concentrations of both drugs were compared to the MICs of the different enterococcal isolates. Conclusions: ABPR is a well-tolerated antimicrobial regimen with anti-E. faecalisactivity. TDM can help clinicians optimize medical treatments to achieve the best possible efficacy with fewer side effects. ABPR might be a reasonable option for the treatment of severe invasive infections caused byE. faecalisdue to the high level of enterococcal penicillin-binding protein (PBP) saturation.