Deep vein thrombosis (DVT) has an annual incidence of 0.2% in the urban population. First episodes of calf vein thrombosis (CVT) and proximal DVT are frequently elicited by risk factors, including varicose veins, cancer, pregnancy/postpartum, oral contraceptives below the age of 50 years, immobility or surgery. Leg pain and tenderness in the calf and popliteal fossa on physical examination may result from other conditions than DVT labeled as alternative diagnosis (AD) Congenital venous thrombophilia is present in every third first DVT, increased FVIII in every fourth first DVT, and FV Leiden/FII mutation in 40% of women on oral anticonceptive pill before reaching the menopause. Routine thrombophilia testing for FV Leiden/prothrombin mutation and FVIII as main risk factor for venous thrombosis is recommended. Primary superficial venous thrombosis (SVT) and DVT patients with a autosomal dominant family history of DVT are candidates for thrombophilia testing for congenital AT, PC and PS deficiency. The requirement for a safe diagnostic strategy of CVT and DVT should be based on an objective post-test incidence of venous thromboembolism (VTE) of less than 0.1% with a negative predictive value for exclusion of DVT of 99.9% during 3 months follow-up. Modification of the Wells score by elimination of the "minus 2 points" for AD is mandatory and will improve the diagnostic accuracy of CVT/DVT suspicion in the primary care setting and outpatient ward. The sequential use of complete DUS, ELISA D-dimer testing and modified clinical Wells' score assessment is safe and effective for the exclusion and diagnosis of CVT, DVT and AD. About 10% to 20% of patients with DVT develop overt post-thrombotic syndrome (PTS) at one year post-DVT, and both PTS and DVT recurrences further increase to about 30% during long-term follow-up. Objective risk stratification of PTS complications using DUS for recanalization and reflux and D-dimer testing will become an integral part in routine clinical practice to assess the optimal duration of wearing medical elastic stockings and anticoagulation for the prevention DVT recurrence as the best option to reduce the incidence and costs of suffering from irreversible PTS.