Background: Rapid D-dimer assays are being used in the diagnostic evaluation of suspected pulmonary embolism (PE). Although this hypothesis is anticipated to decrease the use of ventilation-perfusion (VQ) scans and other diagnostic tests for PE, it has not been tested in a "real-world" environment. Subjects and Methods: A randomized prospective trial was conducted on 470 of the 5390 enrolled patients aged 60 years and older who had previously undergone any diagnostic tests for PE at an urban teaching hospital. The use of D-dimer as part of the diagnostic evaluation for PE was promulgated in the 2 randomly chosen intervention firms. The remaining 2 firms served as controls. Main Outcome Measures: The number of VQ scans, spiral computed tomographic scans, and pulmonary angiograms performed. Secondary outcomes included mortality and thromboembolic or bleeding events during 3 months of follow-up. Results: Of the 470 inpatients who underwent evaluation for PE on a per PE workup basis, fewer VQ scans were performed in the intervention firms (63.8% vs 81.3%; P<.01). However, the number of patients evaluated for PE nearly doubled in the intervention firms (304 vs 166; P<.01), so that more VQ scans were performed in the intervention than in the control firms (194 vs 135; P<.01). Ninety-four patients from the control firms and 160 patients from the intervention firms were diagnosed and treated for venous thromboembolic disease (P<.01). There were no differences in secondary outcomes during the 3-month follow-up. Conclusions: The introduction of a rapid D-dimer assay increased the number of VQ scans performed because the number of patients screened for PE increased. A larger number of patients in the intervention firms were diagnosed as having venous thromboembolic disease (PE and/or deep vein thrombosis). There were no perceived changes in mortality or venous thromboembolic events during the 3-month follow-up.