The effects of various covariate factors on the pharmacokinetics of erythropoietin (EPO) in subjects who are critically ill and admitted to an intensive care unit were evaluated. Nonlinear mixed-effects modeling was used to analyze the data from 48 patients receiving subcutaneous doses of 40,000 IU/wk epoetin alfa enrolled in a randomized, double-blind, placebo-controlled, multicenter study. The pharmacokinetics of EPO follows a 1-compartment disposition model with first-order absorption and an endogenous input rate. For a patient weighing 70 kg, the typical apparent clearance (CL/F) and apparent volume of distribution (V/F) were estimated to be 1.86 L/h and 27.8 L. The interindividual variability in CL/F and V/F was estimated to be 57.2% and 83.8%. CL/F and V/F of EPO increased with body weight, as described by the following relation: CL/F = (CL/F)std*(W/W(std))0.75, and V/F = (V/F)std*(W/W(std))1.37, where W is individual weight, and W(std) is the median weight of the study population. There was a 46% drop in exposure of EPO from the first to the subsequent dosing events. The endogenous EPO production rate was found to decrease progressively with the course of the study. In addition, the modeled endogenous EPO production rate increased with body weight. The net effect of this increase on the endogenous plasma EPO levels may not be significant because EPO clearance was found to increase with body weight. All other factors investigated (eg, Sequential Organ Failure Assessment [SOFA] scores and APACHE II scores) had no significant effect on EPO pharmacokinetics. The typical population estimate of CL/F of EPO was close to previously reported values in healthy volunteers.