Linezolid is a new oxazolidinone antibiotic used to treat infections caused by vancomycin-resistant enterococci (VRE). In early clinical trials, emergence of resistance occurred rarely. We report clinical details and antibiotic susceptibility from five patients treated with linezolid for VRE infections who had resistant organisms isolated during therapy. Four were transplant patients receiving protracted courses of the drug; three cases were associated with treatment failure. One of 45 linezolid-treated patients developed resistance during therapy. Susceptibility testing should be done in all cases on starting therapy.