Abstract A population pharmacokinetic analysis of daptomycin was performed based on therapeutic drug monitoring (TDM) data from 58 patients receiving doses of 4–12 mg/kg for the treatment of severe Gram-positive infections. At a daily dose of 8 mg/kg, daptomycin plasma concentrations (mean ± S.D.) were 76.9 ± 9.8 mg/L at the end of infusion and 52.7 ± 15.4 mg/L and 11.4 ± 5.4 mg/L at 0.5 h and 23 h after drug administration, respectively. The final model was a one-compartmental model with first-order elimination, with estimated clearance (CL) of 0.80 ± 0.14 L/h and a volume of distribution ( Vd ) of 0.19 ± 0.05 L/kg. Creatinine clearance (CLCr ) was identified as having a significant influence on daptomycin CL, and a decrease in CLCr of 30 mL/min from the median value (80 mL/min) was associated with a reduction of daptomycin CL from 0.80 L/h to 0.73 L/h. These results confirm that the presence of severe infection may be associated with an altered disposition of daptomycin, with an increased Vd . MICs were available in 41 patients and results showed that 38 and 31 subjects achieved AUC/MIC values associated with bacteriostatic (>400) and bactericidal effects (>800), respectively. Of note, 31 of these 41 subjects experienced a clinical improvement or were cured. Although daptomycin pharmacokinetics may be influenced by infections, effective AUC/MIC values were achieved in the majority of patients. The present model may be applied in clinical settings for a TDM routine on the basis of a sparse blood sampling protocol.