Summary. Background: The post-thrombotic syndrome (PTS) is a frequent complication of deep vein thrombosis (DVT). Patients with recurrent ipsilateral DVT have an increased risk of PTS; other risk factors are unknown. Objectives: To establish risk factors of PTS and its impact on venous thrombotic disease. Patients: We prospectively followed 406 patients after a first symptomatic DVT for a median of 60 months. Patients with recurrent DVT, a natural inhibitor deficiency, the lupus anticoagulant, cancer, long-term anticoagulation, an observation time < 18 months and DVT-recurrence prior PTS-assessment were excluded. Study outcomes were occurrence of PTS and recurrent symptomatic DVT. Results: PTS was assessed after 44 ± 23 months (mean ± SD) using a clinical classification score. PTS developed in 176 of 406 patients (43.3%). Severe PTS was rare (1.4%). Proximal DVT was the strongest risk factor of PTS [odds ratio (OR) 2.1, 95% confidence interval (CI) 1.3–3.7]. Male gender (OR 1.6, 95% CI 1.0–2.8) and elevated D-dimer levels (OR 1.9, 95% CI 1.0–3.9) were weaker risk factors. Factor V Leiden, factor II G20210A or high factor VIII did not confer an increased risk of PTS. At 4 years, the cumulative probability of recurrence was 7.4% (95% CI 3.2–11.7) among patients with PTS when compared with 1.6% (95% CI 0–3.5; P < 0.02) among patients without PTS. The risk of recurrence was 2.6-fold (95% CI 1.2–5.9) increased when PTS was present. Conclusions: Proximal DVT, male gender, and high D-dimer levels are independently associated with the development of PTS in patients with a first DVT. Patients with PTS have an increased risk of recurrent venous thromboembolism.