Infective endocarditis now comprises an increasingly complex mixture of endocardial infections, with staphylococci as the predominant cause. Although vancomycin has been an important therapeutic option for several decades, reduced susceptibility is emerging. Daptomycin is a relatively new antimicrobial agent, approved for right-sided endocarditis, but the data for other forms of endocarditis are limited. Here we report clinical data from the Leeds Endocarditis Service (Leeds, UK) for 19 patients treated with daptomycin between January 2007 and December 2009. The majority of cases were caused by staphylococci. All patients were treated with 6 mg/kg with a median treatment duration of 29 days. In total, 53% of patients were cured with antimicrobial regimens, which included daptomycin. Four patients (21%) died during therapy or within 30 days of stopping treatment. The current series is representative of everyday clinical practice and reflects the current difficulties in managing endocarditis.