The incidence of newly diagnosed malignancy is increased in patients with unexplained venous thromboembolism during the first year after a thromboembolic event in comparison to controls (odds ratio, 3.9-36). Extensive screening with computed tomography, endoscopy and tumor markers can identify most of these undetected malignancies. However, approximately half of these can also be identified based on a simple clinical evaluation. Extensive screening has no demonstrated benefit and might actually cause harm. This consideration, combined with the economical and psychological costs of extensive screening leads to the decision not to use such screening procedures, unless indicated by clinical circumstances. Thus, it is appropriate to maintain a low threshold of suspicion for malignancy when treating patients with unexplained venous thromboembolism and to base the decision to perform additional diagnostic tests on the findings of an initial medical history, physical examination, routine laboratory tests and chest x-ray.