Background: The long-term risk of major bleeding in patients receiving extended (beyond the initial 3-6 months) anticoagulant therapy for a first unprovoked venous thromboembolism (VTE) is uncertain. Purpose: To determine the incidence of major bleeding during extended anticoagulation up to 5 years among patients with a first unprovoked VTE, overall and in clinically important subgroups. Data Sources: MEDLINE, EMBASE, and the Cochrane CENTRAL from inception to 23 July 2021. Study Selection: Randomized controlled trials (RCTs) and prospective cohort studies reporting major bleeding among patients with a first unprovoked VTE who were to receive oral anticoagulation for a minimum of 6 additional months after completing at least 3 months of initial anticoagulant treatment. Data Extraction: Two reviewers independently abstracted data and assessed study quality. Unpublished data required for analyses were obtained from authors of included studies. Data Synthesis: Among the 14 RCTs and 13 cohort studies included in the analysis, 9982 patients received a vitamin K antagonist (VKA) and 7220 patients received a direct oral anticoagulant (DOAC). The incidence of major bleeding per 100 person-years was 1.74 (95% CI,1.34-2.20) with VKAs and 1.12 (95% CI, 0.72-1.62) with DOACs. The 5-year cumulative incidence of major bleeding with VKA was 6.3% (3.6%-10.0%). Among patients receiving either a VKA or a DOAC, the incidence of major bleeding was statistically significantly higher among those with age >65 years, creatinine clearance <50 mL/min, a history of bleeding,concomitant use of antiplatelet therapy, and hemoglobin <100 g/L. The case-fatality rate of major bleeding was 8.3% (95% CI, 5.1%-12.2%) with VKAs and 9.7% (95% CI, 3.2%-19.2%) with DOACs. Limitation: Insufficient data to estimate incidence of major bleeding beyond 1 year of extended anticoagulation with DOACs. Conclusion: In patients with a first unprovoked VTE, the long-term risks and consequences of anticoagulant-related major bleeding are considerable. This information will help inform patient prognosis and guide decision making about treatment duration for unprovoked VTE. Primary Funding Source: Canadian Institutes of Health Research. Registration: PROSPERO CRD42019128597.