The purpose of this study was to evaluate whether the determination of pretest probability using a simple clinical model and the SimpliRED D-dimer could be used to improve the management of hospitalized patients with suspected deep-vein thrombosis. Consecutive hospitalized patients with suspected deep-vein thrombosis, had their pretest probability determined using a clinical model and had a SimpliRED D-dimer assay. Patients at low pretest probability underwent a single ultrasound test. A negative ultrasound excluded the diagnosis of deep-vein thrombosis whereas a positive ultrasound was confirmed by venography. Patients at moderate pretest probability with a positive ultrasound were treated for deep-vein thrombosis whereas patients with an initial negative ultrasound underwent a single follow-up ultrasound one week later. Patients at high pretest probability with a positive ultrasound were treated whereas those with negative ultrasound underwent venography. All patients were followed for three months for the development of venous thromboembolic complications. Overall, 28% (42/150), and 10% (5/50), 21% (14/71) and 76% (22/29) of the low, moderate and high pretest probability patients. respectively, had deep vein thrombosis. Two of 111 (1.8%; 95% CI = 0.02% to 6.4%) patients considered to have deep vein thrombosis excluded had events during three-month follow-up. Overall 13 of 150 (8.7%) required venography and serial testing was limited to 58 of 150 (38.7%) patients. The negative predictive value of the SimpliRED D-dimer in patients with low pretest probability was 96.2%, which is not statistically different from the negative predictive value of a negative ultrasound result in low pretest probability patients (97.8%). Management of hospitalized patients with suspected deep-vein thrombosis based on clinical probability and ultrasound of the proximal deep veins is safe and feasible.