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Daptomycin, a cyclic lipopeptide antibiotic, displays high plasma protein binding. This study developed the simple method of liquid chromatographic separation using a core–shell octadecylsilyl microparticulate coupled to tandem mass spectrometry for the quantitation of total and free daptomycin in human plasma.Free daptomycin in plasma was obtained by centrifugal ultrafiltration. Deproteinized plasma specimens were directly separated using a core–shell octadecylsilyl microparticulate with isocratic elution. The mass spectrometer was run in positive-ion electrospray ionization mode. This method was applied to the quantitation of plasma samples in patients treated with intravenous daptomycin.Daptomycin and diazepam as an internal standard were eluted with a total run time of 10 minutes. The calibration curves of total and free daptomycin in human plasma were linear over the concentration ranges of 1–100 and 0.1–10 mcg/mL, respectively. The lower limits of quantitation of the total and free daptomycin in human plasma were 1.0 and 0.1 mcg/mL, respectively. Their extraction recovery rates in nonfiltrated and ultrafiltrated plasma samples were 106.1% and 98.2%, respectively. Total and free daptomycin did not exhibit any matrix effects in human plasma. The intraday and interday accuracies and imprecisions of total daptomycin were 88.7%–106.0% and 98.7%–105.9%, and within 4.1% and 10.4%, whereas those of free daptomycin were 86.8%–101.6% and 103.0%–107.8%, and within 14.6% and 14.6%, respectively. The plasma concentration ranges of total and free daptomycin in 15 infected patients were 3.01–34.1 and 0.39–3.64 mcg/mL, respectively. The plasma protein binding rate of daptomycin ranged from 80.8% to 94.9%.The present simple method with an acceptable analytical performance can be helpful for monitoring the pharmacokinetics of daptomycin in infected patients observed in clinical settings.