Background We compared the efficacy and safety of the low-molecular weight heparin enoxaparin with unfractionated heparin (UFH) for the prevention of venous thromboembolic disease in patients with heart failure or severe respiratory disease. Methods This was a multicenter, controlled, randomized, open study in which patients received either enoxaparin (40 mg once daily) or UFH (5000 IU 3 times daily) for 10 ± 2 days in 64 medical departments in Germany. Patients were stratified and enrolled according to their underlying disease: severe respiratory disease or heart failure. The primary efficacy parameter was a thromboembolic event up to 1 day after the treatment period. Results Of the 665 patients enrolled, 451 patients were able to be evaluated in the primary efficacy analysis. The incidence of thromboembolic events was 8.4% with enoxaparin and 10.4% with UFH. Enoxaparin was at least as effective as UFH, with a 1-sided equivalence region of −4% (90% CI −2.5-6.5, P = .015). Enoxaparin was associated with fewer deaths, less bleeding, and significantly fewer adverse events (45.8% vs 53.8%, P = .044). Conclusions Enoxaparin is at least as effective as UFH in the prevention of thromboembolic events in patients with heart failure or severe respiratory disease. Its beneficial safety profile and once-daily administration is advantageous for inpatient and outpatient use. (Am Heart J 2003;145:614-21.)