Despite the development of novel antibiotics active against Gram-positive bacteria, vancomycin generally remains the first treatment, although rapidly achieving concentrations associated with maximal efficacy provides an unresolved challenge. The objective of this study was to conduct a population pharmacokinetic analysis of vancomycin in a large population of critically ill patients. This was a retrospective data collection of 206 adult septic critically ill patients who were administered vancomycin as a loading dose followed by continuous infusion. The concentration-versus-time data for vancomycin in serum was analyzed by a nonlinear mixed-effects modeling approach using NONMEM. Monte Carlo simulations were performed using the final covariate model. We found that the best population pharmacokinetic model consisted of a one-compartment linear model with combined proportional and additive residual unknown variability. The volume of distribution of vancomycin (1.5 liters/kg) was described by total body weight and clearance (4.6 liters/h) by 24-hour urinary creatinine clearance (CrCl), normalized to body surface area. Simulation data showed that a 35-mg/kg loading dose was necessary to rapidly achieve vancomycin concentrations of 20 mg/liter. Daily vancomycin requirements were dependent on CrCl, such that a patient with a CrCl of 100 ml/min/1.73 m² would require at least 35 mg/kg per day by continuous infusion to maintain target concentrations. In conclusion, we have found that higher-than-recommended loading and daily doses of vancomycin seem to be necessary to rapidly achieve therapeutic serum concentrations in these patients.