Of 1330 outpatients with suspected deep vein thrombosis (DVT), a normal enzyme-linked immunosorbent assay (ELISA) d-dimer (VIDAS) of <500 ng/mL was true negative in 382 of 384 and false negative in compression ultrasonography (CUS) in 2, indicating a sensitivity of 99.52% and a negative predictive value (NPV) of 99.48%, with a specificity of 36% irrespective of clinical score. In 1059 outpatients with no DVT, the CUS was positive for the alternative diagnoses (AD): Bakers cyst, muscle hematoma, or old DVT in 62 (5.8%); superficial vein thrombosis without DVT in 78 (7.4%), and leg edema or varices in 17%. A second CUS in 641 patients was positive in 26 (4.0%), indicating an NPV of 96% after a first negative CUS. The NPV of the combination of a negative first CUS and a ELISA d-dimer test <1000 ng/mL was 99.1% at a specificity of 66.9%. As this strategy is cost effective by reduction in the need to repeat CUS by 67%, we designed a novel algorithm for the safe exclusion and diagnosis of DVT and AD for subsequent evaluation in a large prospective study.