No mutant-prevention concentration (MPC) with methicillin-resistant Staphylococcus epidermidis (MRSE) has been reported. The study aimed to evaluate the propensity of vancomycin individually and in combination to prevent MRSE from mutation. A total of 10 MRSE clinical isolates were included in the study. Susceptibility testing demonstrated that the susceptibility rates to vancomycin, rifampicin, levofloxacin and fosfomycin were 100, 100, 50 and 90%, respectively. The fractional inhibition concentration indices (FICI) for vancomycin combined with rifampicin, levofloxacin or fosfomycin were ≥1.5 but ≤2, ≥1.5 but ≤2, and >0.5 but ≤1.5, respectively, implying indifferent interactivity. The MPC with susceptible strains was determined to be the lowest antibiotic concentration inhibiting visible growth among 10(10) CFU on four agar plates (9 cm in diameter) after a 72-h incubation at 37°C. The MPCs were 16~32, >64, ≥64 and 4~16 μg ml(-1) for vancomycin, rifampicin, fosfomycin and levofloxacin, respectively. The vancomycin MPCs of combinations with fosfomycin (32 μg ml(-1)), levofloxacin (2 μg ml(-1)) and rifampicin (2 or 4 μg ml(-1)) were 1~4, 16~32 and 16~32 μg ml(-1), respectively. Against mutants selected by vancomycin, rifampicin, levofloxacin and fosfomycin individually, antibiotics had standard MICs of 2~4 μg ml(-1) for vancomycin, >64 μg ml(-1) for rifampicin, 4~8 μg ml(-1) for levofloxacin and 64 μg ml(-1) for fosfomycin. Thus single-step mutation can lead to resistance of MRSE to rifampicin, levofloxacin and fosfomycin, rather than non-susceptibility to vancomycin. Vancomycin-fosfomycin combination might be a superior alternative to vancomycin in blocking the growth of MRSE mutants, especially for high-organism-burden infections.