CONTEXT: Patients with venous thromboembolism (VTE) are susceptible to recurrent events, but whether prolonging anticoagulation is warranted in patients with VTE remains controversial. OBJECTIVE: To review the available evidence and quantify the risks and benefits of extending the duration of anticoagulation in patients with VTE. DATA SOURCES: PubMed, EMBase Pharmacology, the Cochrane database, clinical trial Web sites, and a hand search of reference lists. STUDY SELECTION: Included studies were randomized controlled trials with results published from 1969 through 2004 and evaluating the duration of anticoagulation in patients with VTE that measured recurrent VTE. Excluded studies were those enrolling only pure populations of high-risk patients. Two independent reviewers assessed each article for inclusion and exclusion criteria, with adjudication by a third reviewer in cases of disagreement. Fifteen of 67 studies were included in the analysis. DATA EXTRACTION: Two independent reviewers performed data extraction using a standardized form, with adjudication by the remainder of the investigators in cases of disagreement. Data regarding recurrent VTE, major bleeding, person-time at risk, and study quality were extracted. DATA SYNTHESIS: If patients in the long-term therapy group remained receiving anticoagulation, the risk of recurrent VTE with long- vs short-term therapy was reduced (weighted incidence rate, 0.020 vs 0.126 events/person-year; rate difference, -0.106 [95% confidence interval (CI), -0.145 to -0.067]; P<.001; pooled incidence rate ratio [IRR], 0.21 [95% CI, 0.14 to 0.31]; P<.001). If anticoagulation in the long-term therapy group was discontinued, the risk reduction was less pronounced (weighted incidence rate, 0.052 vs 0.072 events/person-year; rate difference, -0.020 [95% CI, -0.039 to -0.001]; P = .04; pooled IRR, 0.69 [95% CI, 0.53 to 0.91]; P = .009). The risk of major bleeding with long- vs short-term therapy was similar (weighted incidence rate, 0.011 vs 0.006 events/person-year; rate difference, 0.005 [95% CI, -0.002 to 0.011]; P = .14; pooled IRR, 1.80 [95% CI, 0.72 to 4.51]; P = .21). CONCLUSIONS: Patients who receive extended anticoagulation are protected from recurrent VTE while receiving long-term therapy. The clinical benefit is maintained after anticoagulation is discontinued, but the magnitude of the benefit is less pronounced.