Daptomycin (Cubicin; Cubist Pharmaceuticals, Inc., Lexington, MA) is a first-in-its-class cyclic lipopeptide approved for the treatment of patients with complicated skin and skin-structure infections due to susceptible gram-positive pathogens and recently approved for Staphylococcus aureus bloodstream infections including right-sided infective endocarditis. The clinical experience of patients registered in the Cubicin Outcomes Registry and Experience (CORE) 2004 database with daptomycin-treated infective endocarditis is described. The registry data were collected retrospectively by trained investigators to document real-world clinical experience. Study limitations included uncontrolled diagnostic criteria, noncomparative data, and lack of follow-up assessments. A total of 49 patients had a diagnosis of endocarditis: 38 with left-sided or both left-sided and right-sided endocarditis, and 11 with right-sided endocarditis alone. Renal failure was the most common comorbid condition. In all, 27 (55%) of the 49 patients had an initial creatinine clearance of ≤30 mL/min, and 14 (29%) were supported by dialysis. Staphylococcus aureus (59%; 83%, methicillin resistant) and enterococci (29%; 43%, vancomycin resistant) were the most commonly identified pathogens. In most instances, patients received gram-positive therapy before receiving daptomycin (43 of 49 [88%]). The median starting dose of daptomycin was 6 mg/kg (range, 4 to 7 mg/kg); 27 (55%) of the patients received a dose of ≥6 mg/kg. Daptomycin therapy was successful for 31 (63%) of the patients: cure was seen in 18 (37%) and improvement in 13 (27%). Therapy failed in 4 (8%) of the patients, and 14 (29%) of the cases were nonevaluable. The median duration of therapy in successful cases was 27 days. No differences in clinical response were observed based on baseline renal function, primary pathogen, or site of endocarditis. The results from the CORE 2004 database suggest that daptomycin should be considered a possible treatment for patients with right-sided infective endocarditis involving S aureus. Further studies are needed to extend daptomycin’s experience in left-sided or enterococcal endocarditis.