The aim of the study was to determine factors associated with spread of linezolid (LNZ)-resistant Staphylococcus epidermidis isolates in a surgical intensive care unit (ICU). A case-control study was conducted in one French adult surgical ICU. From January 2012 to December 2016, patients with at least a single positive LNZ-resistant S. epidermidis blood culture were matched to control with LNZ-susceptible S. epidermidis blood culture in a 1:4 manner. Cases were compared to controls regarding baseline clinical characteristics and LNZ exposure before positive blood culture. Bacterial isolates were genotyped by using pulsed-field gel electrophoresis (PFGE) and MLST. We identified 13 LNZ-resistant S. epidermidis isolates, 1 in 2012, 3 in 2014, 6 in 2015, and 3 in 2016. LNZ use increased steadily from 8 DDDs/100 patient days in 2010 to 19 in 2013 and further decrease by more of 50% in 2015 and 2016. The only independent risk factors associated to LNZ-resistant S. epidermidis isolation were length of stay in ICU before infection (OR 1.45; 95% CI 1.07-1.98), prior exposure to LNZ (OR 109; 95% CI 3.9-3034), and Charlson comorbidities score (OR 3.19; 95% CI 1.11-9.14). PFGE typing showed that all LNZ-resistant isolates were clonal belonging to ST2 and that LNZ-susceptible isolates were highly diverse. We report herein that previous exposure to LNZ substantially increased the risk of occurrence of LNZ resistance in S. epidermidis even in the case of clonal spread of LNZ-resistant isolates. These findings highlight the need for reducing the use of LNZ to preserve its efficacy in the future.