The new oxazolidinone antimicrobial, linezolid (LZD), has been approved for the treatment of infections caused by grampositive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococci (VRE). Though LZD-resistant strains have been reported in Europe and the United States, none have yet been discovered in Japan. We report the case of a patient with intractable retroperitoneal abscess infected with E. faecium who was initially treated successfully with LZD but E. faecium subsequently exhibited resistance to LZD. The patient was a 66-year-old female in whom most of the E. faecium infection was detected in the retroperitoneum. Neither teicoplanin (TEIC) nor vancomycin (VCM) had any effect so LZD was then administered at a dose of 1,200 mg/day. The subsequent clinical course was good but following withdrawal of LZD, the infection recurred and was aggravated. The administration of LZD was restarted and the patient recovered when it was continued over the long-term. However, during this period E. faecium became LZD-resistant with the resistance stemming from a G2576 T mutation of the 23S rRNA gene, which suggests that long-term administration can be a tolerance-related risk factor and that LZD induces the resistance mechanism at a certain frequency of use. Pharmacists responsible for infection control should therefore conduct sensitivity testing on isolates from the beginning of LZD treatment to monitor for resistance to LZD.