In primary care, the physician has to decide which patients have to be referred for further diagnostic work-up. At present, only in 20% to 30% of the referred patients the diagnosis DVT is confirmed. This puts a burden on both patients and health care budgets. The question arises whether the diagnostic work-up and referral of patients suspected of DVT in primary care could be more efficient. A simple diagnostic decision rule developed in primary care is required to safely exclude the presence of DVT in patients suspected of DVT, without the need for referral. In a cross-sectional study, we investigated the data of 1295 consecutive patients consulting their primary care physician with symptoms suggestive of DVT, to develop and validate a simple diagnostic decision rule to safely exclude the presence of DVT. Independent diagnostic indicators of the presence of DVT were male gender, oral contraceptive use, presence of malignancy, recent surgery, absence of leg trauma, vein distension, calf difference and D-dimer test result. Application of this rule could reduce the number of referrals by at least 23% while only 0.7% of the patients with a DVT would not be referred. We conclude that by using eight simple diagnostic indicators from patient history, physical examination and the result of D-dimer testing, it is possible to safely rule out DVT in a large number of patients in primary care, reducing unnecessary patient burden and health care costs.