BACKGROUND: The risk of major bleeding in patients who have completed anticoagulation therapy for unprovoked venous thromboembolism (VTE) is unknown. OBJECTIVE: To report the major bleeding and fatal bleeding rates in patients randomized to placebo or observation (i.e. no anticoagulation therapy) for the secondary prevention of recurrent VTE. PATIENTS/METHODS: We performed a systematic review and meta-analysis of the literature to summarize the rates of major bleeding and fatal bleeding in patients randomized to placebo or observation during the secondary prevention of VTE. Unrestricted searches of Medline (1950 to August 31, 2013), Embase (1980 to August 31, 2013), and the Cochrane Register of Controlled Trials using the OVID interface were conducted. Publications from potentially relevant journals were also searched by hand. We used a random-effects model to pool study results and I(2) testing to assess for heterogeneity. RESULTS: The analysis included 11 studies and 3,965 patients who were followed for a median of 24 months. The overall pooled major bleeding rate was 0.45 per 100 patient-years (95% CI: 0.29 to 0.64; I(2) : 0%), and the overall pooled fatal bleeding rate was 0.14 per 100 patient-years (95% CI: 0.057 to 0.26; I(2) : 0%). CONCLUSIONS: Patients not receiving anticoagulant therapy for the secondary prevention of VTE experience major bleeding events and this may impact recommendations for extended treatment in this patient population. This article is protected by copyright. All rights reserved.