OBJECTIVE To prospectively validate the HERDOO2 rule (Hyperpigmentation, Edema, or Redness in either leg; D-dimer level >= 250 mu g/L; Obesity with body mass index >= 30; or Older age, >= 65 years), which states that women with none or one of the criteria can safely discontinue anticoagulants after short term treatment. DESIGN Prospective cohort management study. SETTING 44 secondary or tertiary care centres in seven countries. PARTICIPANTS Of 3155 consecutive eligible participants with a first unprovoked venous thromboembolism (VTE, proximal leg deep vein thrombosis or pulmonary embolism) who completed 5-12 months of short term anticoagulant treatment, 370 declined to participate, leaving 2785 enrolled participants. 2.3% were lost to follow-up. INTERVENTIONS Women with none or one of the HERDOO2 criteria were classified as at low risk of recurrent VTE and discontinued anticoagulants (intervention arm), whereas anticoagulant management for high risk women (>= 2 HERDOO2 criteria) and men was left to the discretion of the clinicians and patients (observation arm). MAIN OUTCOME MEASURE Recurrent symptomatic VTE (independently and blindly adjudicated) over one year of follow-up. RESULTS Of 1213 women, 631 (51.3%) were classified as low risk and 591 discontinued oral anticoagulant treatment. In the primary analysis, 17 low risk women who discontinued anticoagulants developed recurrent VTE during 564 patient years of follow-up (3.0% per patient year, 95% confidence interval 1.8% to 4.8%). In 323 high risk women and men who discontinued anticoagulants, 25 had VTE during 309 patient years of follow-up (8.1%, 5.2% to 11.9%), whereas in 1802 high risk women and men who continued anticoagulants 28 had recurrent VTE during 1758 patient years of follow-up (1.6%, 1.1% to 2.3%). CONCLUSIONS Women with a first unprovoked VTE event and none or one of the HERDOO2 criteria have a low risk of recurrent VTE and can safely discontinue anticoagulants after completing short term treatment.