Enoxaparin is commonly used to prevent venous thromboembolism(VTE) [1,2] but has not been well-studied in patients with extreme obesity,a population at high risk for VTE. We prospectively compared three enoxaparin dosing regimens for the achievement of goal peak anti-Factor Xa levels in medically ill patients (n 5 31) with extreme obesity (body mass index (BMI) ‡ 40 kg/m2). Patients were assigned to receive fixed-dose (FD) enoxaparin 40 mg daily (QDay, n 5 11), weight based,lower-dose (LD) enoxaparin 0.4 mg/kg QDay (n 5 9), or weight based,higher-dose (HD) enoxaparin 0.5 mg/kg QDay (n 5 11). The average BMI and weight of the entire cohort was 62.1 kg/m2 (range40.5–82.4) and 176 kg (range 115–256 kg) and did not differ between groups. Peak anti-Factor Xa levels were significantly higher in the HD group compared to either LD or FD groups. Patients in the HD group achieved target anti-Factor Xa levels more frequently than the LD and FD groups (P < 0.05). Peak anti-Factor Xa levels did not correlate with age, weight, BMI, or creatinine clearance, demonstrating the predictability of weight-based enoxaparin dosing. There were no adverse events (e.g., bleeding, thrombosis, thrombocytopenia). To our knowledge this is the first prospective comparative study demonstrating that in extremely obese, medically ill patients enoxaparin 0.5 mg/kg QDay is superior to FD and LD enoxaparin for the achievement of target anti-Factor Xa levels.