We compared the activity of daptomycin, vancomycin and fluoroquinolones against 46 blood isolates of Staphylococcus epidermidis. Daptomycin was more rapidly bactericidal than vancomycin and demonstrated less of an inoculum effect than the quinolones. Time-kill kinetic studies demonstrated no significant differences in survival in broth as compared to 50% human serum-supplemented broth. Daptomycin and the quinolones are suitable for study in clinical trials of efficacy as therapeutic alternatives to vancomycin for S. epidermidis infections.