Catheter-related bloodstream infections due to slow-growing Staphylococcus epidermidis small-colony variants (SCVs) are extremely difficult to treat. Daptomycin and vancomycin pharmacodynamics were evaluated against a site-directed hemB mutant of S. epidermidis displaying the SCV phenotype and compared to that of the parental strain. The maximal killing effect decreased by 7.7-fold for vancomycin and 1.5-fold for daptomycin against the SCV mutant and were well characterized by a Hill-type mathematical model (R2 > 0.97).