Objective: Guidelines recommend low-dose unfractionated heparin (UFH) and low-molecular-weight heparin for the prophylaxis of venous thromboembolism (VTE) in acutely ill medical patients. We report the findings of an openlabel, active-controlled, multicenter study in acutely ill medical patients comparing certoparin and UFH. Research design and methods: Open-label, active-controlled, multicenter study. Patients received certoparin 3000 IU daily or UFH 7500 IU twice daily. Main outcome measures: The primary endpoint was a composite of symptomatic or asymptomatic proximal or distal deep vein thrombosis, symptomatic pulmonary embolism, or VTE-related death. Results: 172 patients were randomized to UFH and 163 to certoparin for 8.5 ± 2.1 days. The incidence of the primary endpoint was 18.0% in patients receiving UFH and 10.7% with certoparin [absolute difference -7.3; 95% confidence interval (CI) -16.9 to 2.3; p = 0.1353]. The incidence during follow-up was 2.6% in the UFH and 2.0% in the certoparin group (absolute difference -0.6; 95%CI -4.0 to 2.8; p = 0.7150). Major bleeding events occurred in three patients with UFH and one patient with certoparin. Conclusions: In acutely ill medical patients of at least 40 years of age, thromboprophylaxis with certoparin 3000 IU daily is effective and safe in comparison with 7500 IU twice daily UFH.