Tigecycline is a glycylcycline antibiotic that inhibits protein synthesis, including that in isolates resistant to tetracyclines by ribosomal protection or efflux. Infrequently, strains of enterobacteria have been reported as resistant to tigecycline due to overexpression of multidrug efflux pumps such as AcrAB. This report describes the development and mechanism of resistance to tigecycline during therapy for an Enterobacter hormaechei infection associated with lack of clinical response. A 47-year-old man with end-stage hepatic failure was treated with tigecycline for E. hormaechei UCN62 infection after liver transplantation. After 3 weeks, isolate UCN63 from bile showed reduced tigecycline susceptibility (MIC increased from 2 to 4 g/ml). Pulsed-field gel electrophoresis and ribotyping confirmed both isolates as E. hormaechei subsp. steigerwaltii. Reverse transcription-PCR revealed an approximately 8-fold increase in acrA expression in UCN63 compared to UCN62. This study found that the increase in MIC correlated with overexpression of the multidrug efflux pump AcrAB.