Background <p>Daptomycin has a favorable efficacy and safety profile against enterococcal infections, but it is currently a last line treatment for enterococcal infective endocarditis (EIE) due to limited evidence supporting its use.</p> Methods <p>This study aimed to investigate clinical outcomes among patients with EIE who received daptomycin versus beta-lactam based therapy. This was a single-center, retrospective cohort study of hospitalized patients with documented EIE and definitive treatment with daptomycin or beta-lactam based therapy between 2011 and 2023. The primary outcome was clinical failure (composite of inpatient infection-related mortality and progression of disease leading to change in therapy). Descriptive statistics assessed baseline demographics, clinical data, and outcomes between patients who received daptomycin versus beta-lactams.</p> Results <p>Twenty-six patients receiving daptomycin (median 10&#xa0;mg/kg/dose) were compared to 102 receiving beta-lactam based therapy (81% ampicillin and ceftriaxone). No significant difference in clinical failure was observed between groups (0% daptomycin vs. 6% beta-lactam; <i>p</i> = 0.35). Individual components of the primary outcome, all-cause mortality, and adverse events leading to therapy discontinuation were similar between groups.</p> Conclusions <p>Outcomes were similar among patients with EIE treated with daptomycin versus beta-lactams. Larger, prospective studies are needed to confirm this finding.</p>