Despite the use of a clinical score and D-dimers to exclude deep vein thrombosis (DVT), the majority of patients still need repeated ultrasound (US). The aim of the study was to investigate whether fibrin monomers (FMs), as markers of thrombin generation, have additional value in the diagnosis of DVT. This is a posthoc analysis of 464 outpatients, participants in a management study using D-dimers (Tina-Quant and a clinical score in the exclusion of DVT. Two new FM assays (Auto LIA-FM and IATRO SF, Japan) were performed. Overall sensitivity, negative predictive value (NPV) and specificity of the D-dimer test were 98%, 98% and 42%. The optimal cut-off point for the Auto LIA-FM test was <or=3 microg/ml with values of 88%, 88% and 59%, respectively. The IATRO SF test had an optimal cut-off point of <or=2 microg/ml with values of 92%, 81 and 22%, respectively. The NPV of a non-high clinical score and a normal D-dimer (n=97) was 100%. In patients with a high clinical score (n=160), the NPV of the D-dimer was 88%. In these patients, a single US combined with a normal D-dimer or FM test had an equal NPV as serial US (100 versus 98%, respectively) and lead to a reduction in the need for US by 36-53%, respectively. In patients with abnormal D-dimer concentrations (n=343), a normal US combined with a normal Auto LIA-FM test had a NPV of 97%, which was also true for serial US. This could lead to a reduction in the need for US by 45%. The present studied FMs are inferior to the Tina-Quant D-dimer test when used as primary screening tool to exclude DVT. Adding these FMs to patients with a normal Tina-Quant D-dimer has no benefit. In patients with a high pretest clinical probability score, a single US in combination with a normal D-dimer or FM test might be as safe as serial US. In patients with abnormal D-dimer concentrations and a normal US, a normal FM test might be able to replace the second US.