Reports of linezolid resistance among Enterococcus faecalis have been relatively rare. We describe three patients with linezolid-resistant strains of E. faecalis, discovered after the patients had received long courses (> 30 days) of linezolid therapy. All strains contained the G2576U mutation in 23S rRNA. A literature review revealed one other case in the United States and three cases in Europe; all involved patients who had received long courses of therapy. It appears that recent or extended linezolid therapy may be a risk factor for development of resistant E. faecalis. In patients who have recently been treated with linezolid and have an identified new systemic enterococcal isolate, linezolid sensitivity should be verified as soon as possible to guide therapy. This strategy also should be considered for patients with a breakthrough enterococcal isolate during linezolid therapy.