Enoxaparin is the only low molecular-weight heparin (LMWH) with documented efficacy for the prevention of venous thromboemobolism (VTE) following trauma, and it is currently considered the treatment of choice. Recent reports have suggested that the pharmacokinetics (PK) and pharmacodynamics of LMWH products may be altered in critically ill patients. Two cohorts of critically ill multiple trauma patients were enrolled in this study: A (nonedematous) and B (edematous, defined as the presence of peripheral edema and an increase in body weight of > or =10 kg). All patients received at least four doses of enoxaparin 30 mg subcutaneously every 12 hours before the study dose. Blood samples were collected before and 0.5, 1, 2, 3, 4, 6, 8, and 12 hours following a morning dose. Plasma anti-Xa and antithrombin (AT) activities were determined using chromogenic assays. A compartmental PK analysis model was defined for the data. PK parameters for the two cohorts were compared using a Mann-Whitney Rank Sum test. The area under the curve (AUC)0-12 hour, maximal plasma anti-activated Factor Xa (anti-Xa) activity (Amax), and AT activity were significantly lower in the edematous trauma patients (p < 0.05). The AUC0-12 hour for plasma anti-Xa activity was highly variable in both study cohorts. Seven of the 10 edematous patients had barely quantifiable anti-Xa results. Activity levels were too low to reliably estimate the PK parameters for most patients in cohort B. The standard dose of enoxaparin recommended for the prevention of VTE following multiple trauma provides unreliable and highly variable anti-Xa activity in critically ill trauma patients, and is strongly affected by the presence of significant peripheral edema.