Linezolid (LZD) has been used for the treatment of nosocomial and community-acquired pneumonia, as well as complicated skin and soft-tissue infection caused by methicillin-resistant Staphylococcus aureus (MRSA), including vancomycin (VCM)-intermediate S. aureus (VISA). Since VISA tends to exhibit cross-resistance to some anti-MRSA agents, such as teicoplanin and daptomycin, we evaluated the in vitro activity of LZD toward VISA strains isolated from various countries of the world. During susceptibility tests, we noticed the LZD MIC was relatively low for VISA clinical strains compared to VCM-susceptible S. aureus (VSSA). To confirm this phenomenon, we compared VCM and LZD MICs for 47 VSSA and 43 VISA strains, which confirmed a significant inverse relationship of VCM and LZD susceptibilities between VSSA and VISA. To further confirm, we evaluated the VCM and LZD MICs for 15 isogenic sets of VISA strains, their passage-derived VCM-susceptible strains, and VISA phenotypic revertant strains, and an inverse relationship was again observed, with a correlation coefficient of 0.628 (P 0.01). Finally, we generated isogenic strains from the VCM-susceptible laboratory strain N315LR5-P1 with gradual increments of VCM concentrations, and found that derivative strains with higher VCM resistance had greater susceptibility to LZD and vice versa. Taken together, the results show a negative correlation between VCM and LZD susceptibilities in MRSA, which seems to reveal a weakness of VISA posed by its vancomycin resistance mechanism and might provide a hint for developing a new strategy in the treatment of VISA infection.