The Medical Patients with Enoxaparin (MEDENOX) trial was a randomized, placebo-controlled study that defined the risk of venous thromboembolism (VTE) in acutely ill, immobilized, general medical patients and the efficacy of the low-molecular-weight heparin, enoxaparin, in preventing thrombosis. We performed a post-hoc analysis to evaluate the effect of 40 mg enoxaparin once daily on MEDENOX patient outcome in different types of acute medical illness (heart failure, respiratory failure, infection, rheumatic disorder and inflammatory bowel disease) and pre-defined risk factors (chronic heart and chronic respiratory failure, age, immobility, previous VTE and cancer). The primary outcome was the occurrence of documented VTE between days 1 and 14. The relative risk reduction [95% confidence intervals (CI)] for VTE comparing 40 mg enoxaparin with placebo in the subgroups were: acute heart failure, 0.29 (95% CI, 0.10–0.84); acute respiratory failure, 0.25 (95% CI, 0.10–0.65); acute infectious disease, 0.28 (95% CI, 0.09–0.81); and acute rheumatic disorder, 0.48 (95% CI, 0.11–2.16). The relative risk reduction for VTE in the pre-defined risk factor subgroups were: chronic heart failure, 0.26 (95% CI, 0.08–0.92); chronic respiratory failure, 0.26 (95% CI, 0.10–0.68); age, 0.22 (95% CI, 0.09–0.51); immobility, 0.53 (95% CI, 0.14–1.72); previous VTE, 0.49 (95% CI, 0.15–1.68); and cancer, 0.50 (95% CI, 0.14–1.72). The beneficial effects of enoxaparin extend to a wide range of acutely ill medical patients.