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Abstract: In this study, we assessed by broth microdilution the in vitro activity of oritavancin, a semisynthetic lipoglycopeptide currently under development, against selected meticillin-resistant Staphylococcus aureus (MRSA) bloodstream isolates (n =56) from Geneva University Hospital, Switzerland, displaying a wide range of vancomycin minimum inhibitory concentrations (MICs) (0.25–4μg/mL). The MRSA resistance phenotype was confirmed by broth microdilution (oxacillin MIC ≥4μg/mL) for all isolates; 89% and 100% of the tested isolates were also resistant to erythromycin and ciprofloxacin, respectively. For 53 MRSA isolates for which vancomycin MICs were in the susceptible range (0.5–2.0μg/mL), the oritavancin MICs ranged from 0.03μg/mL to 0.5μg/mL. For these 53 vancomycin-susceptible isolates, the cumulative distribution of oritavancin MICs was markedly different from those of vancomycin, teicoplanin, daptomycin and linezolid MICs, yielding an oritavancin MIC for 90% of the organisms (MIC90) (0.25μg/mL) that was four times lower than the MIC90 values (1μg/mL) of comparators. For three MRSA isolates with a vancomycin-intermediate phenotype (vancomycin MIC=4μg/mL), oritavancin MICs (0.5–1.0μg/mL) were 2–4-fold lower than vancomycin, teicoplanin or daptomycin MICs, but were equivalent to linezolid MICs. Pairwise comparison for each bloodstream isolate showed that oritavancin was ≥4-fold more active than vancomycin, teicoplanin and daptomycin, against 86%, 75% and 59% of all MRSA isolates, respectively. [Copyright &y& Elsevier]