We evaluated six D-dimer methods to determine their sensitivity, specificity, and negative predictive values (NPV) in symptomatic patients suspected of deep vein thrombosis (DVT). In patients suspected of DVT a whole blood D-dimer test (SimpliRED, Agen) was performed, and then tested using enzyme-linked immunosorbent assay (VIDAS D-Dimer, BioMerieux; Asserachrome D-Di, Stago International; Dimertest Gold, Agen) and automated immunoturbidometric methods (Advanced D-Dimer, Dade Behring; MiniQuant, Biopool). Each D-dimer method was independently compared with radiographic results to determine sensitivity and NPV. There were 151 patients enrolled in the study. Thirty-five (23.2%) patients had a positive Doppler ultrasound, with 26 proximal, eight distal, and one patient with both proximal and distal thrombus. Two patients (1.3%) had inconclusive studies and were excluded from the analyses. For all patients, the sensitivities for the rapid D-dimer methods were: SimpliRED, 82.3% [95% confidence interval (CI), 80.3–84.3%]; VIDAS D-Dimer, 91.4% (95% CI, 89.9–92.9%); MiniQuant D-Dimer, 96.3% (95% CI, 95.1–97.5%); and Advanced D-Dimer, 97.1% (95% CI, 96.3–97.9%). The sensitivity improved for SimpliRED (86.4%; 95% CI, 83.3–89.4%), VIDAS D-Dimer (95.5%; 95% CI, 85.0–100%), MiniQuant D-Dimer (100%; 95% CI, 96.9–100%) and Advanced D-Dimer (100%; 95% CI, 98.9–100%) in the inpatient population. The automated immunoturbidometric methods, the MiniQuant D-Dimer and Advanced D-Dimer, demonstrated comparable sensitivities and NPV with the VIDAS D-Dimer method in symptomatic patients suspected of DVT, which would suggest that these newer D-dimer methods could be used as part of the diagnostic algorithm for patients suspected of DVT.