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We report 2 sisters with hyper-IgE syndrome treated with daily suppressive dosages of linezolid (LZD) who developed LZD-resistant Staphylococcus aureus carrying the G2576T mutation in the 23S rRNA gene. Molecular typing suggested transmission of the resistant strain from one sister to the other. LZD-susceptible S. aureus was isolated 2 months after LZD discontinuation. LZD-resistant S. aureus remains rare but may occur while receiving suppressive therapy.