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D-dimer, a breakdown product of cross-linked fibrin has been extensively evaluated as a diagnostic test for acute venous thromboembolism. Rapid, highly sensitive D-dimer assays are now available that are suitable for testing in the emergency setting. Preliminary studies suggest that when using a highly sensitive D-dimer assay, a negative test result may be sufficient to exclude the diagnosis of venous thromboembolism without need for further testing. Less sensitive, but more specific D-dimer assays are also available. The negative predictive value of these latter assays is insufficient to exclude venous thromboembolism on the basis of a negative test result alone. However, their utility is increased by identifying patient populations at low risk for venous thromboembolism using consideration of clinical probability or radiographic testing. Further, large multicenter management studies are required to confirm the safety of relying on a negative D-dimer result to exclude the diagnosis of venous thromboembolism.