The pharmacokinetic profile of heparin may result in supratherapeutic antifactor-Xa levels using total weight-based protocols for the treatment of venous thromboembolism (VTE) in obese patients. Previous literature has been limited by choice of monitoring assay and inconsistent dosing strategies. The goal of this study was to evaluate safety and efficacy outcomes of an antifactor-Xa based UFH VTE protocol in obese vs. non-obese patients. This was a single center, retrospective study of adult patients with an acute VTE treated with our institution specific UFH VTE protocol. Patients were screened from the preceding 3 years for inclusion into the obese (BMI ≥ 30 kg/m2) or non-obese (BMI < 30 kg/m2) groups. The primary outcome was the weight-based rate of UFH (units/kg/hr) required to attain a therapeutic anti-Xa level. Secondary outcomes included rate required to attain steady state, time to first therapeutic anti-Xa level and steady state, proportion of patients to attain at least one therapeutic anti-Xa level and steady state, number of rate changes required to attain steady state, and proportion of anti-Xa levels being therapeutic, subtherapeutic, or supratherapeutic at the first anti-Xa level drawn, within the first 24 h of treatment, and for the duration of treatment with UFH. Safety outcomes evaluated the incidence of any major or non-major bleeding event, requiring reversal agents, or having additional thrombotic events. The primary outcome of weight-based rate at first therapeutic anti-Xa level was significantly lower in the obese group, and this was consistent for attainment of steady state, as well (14 units/kg/hour vs. 16 units/kg/hour, p < 0.001). Patients in the obese group had significantly more supratherapeutic anti-Xa levels within 24 h (50% vs. 33%, p < 0.0001) and for the total duration of UFH therapy (40% vs. 25%, p < 0.0001) No significant differences in clinically overt bleeding rates were found. Obese patients required a lower weight-based rate of UFH to attain therapeutic anti-Xa levels for the treatment of VTE. Additionally, there appears to be an inverse relationship between weight-based UFH rate and total UFH rate at the first therapeutic anti-Xa and steady state as BMI increases. Future studies should focus on dosing strategies that improve attainment of therapeutic anti-Xa levels in obese patients.