The authors compared the population pharmacokinetics of fentanyl using a standard individualized modeling (SIM) approach versus that of a nonparametric expectation maximization (NPEM) approach. The pharmacokinetic properties of fentanyl administered as a single 5 ug/kg intravenous infusion were evaluated in 18 healthy volunteers by use of SIM as well as with NPEM. NPEM-derived parameters were a total body clearance of 2.12 +/- 0.28 L/kg/h, distributional clearance of 8.43 +/- 4.58 L/kg/h, central volume of distribution of 1.22 +/- 0.21 L/kg, and peripheral volume of distribution of 1.81 +/- 1.47 L/kg. Identified parameter values from the modeling methods resulted in virtually identical simulated profiles; this finding was confirmed when median values noted were not statistically significantly different between modeling methods (SIM or NPEM). However, the NPEM algorithm uniquely identified a greater distributional clearance in the elderly population and also illustrated a profile with at least 10% of the study population having a very high clearance of fentanyl. This finding may affect the therapeutic use of fentanyl. NPEM allows for a more informative global representation of a drug's pharmacokinetics.