Laboratory evidence of antiphospholipid antibodies (APLA) in patients with a first episode of venous thromboembolism (VTE) is often considered an indication for indefinite anticoagulant therapy, but it is uncertain if this practice is justified. We performed a systematic review to determine whether the presence of APLA in patients with a first VTE is associated with an increased risk of recurrence. We searched PubMed, CINAHL, Cochrane, EMBASE, and Web of Knowledge through February 2012 and included prospective studies that met prespecified design criteria. There were 109 recurrent VTE in 588 patients with APLA and 374 recurrent VTE in 1914 patients without APLA (relative risk 1.41; 95% confidence interval [CI], 0.99 to 2.36). The unadjusted risk ratio for recurrent VTE after stopping anticoagulant therapy in patients with an anticardiolipin antibody was 1.53 (95% CI, 0.76-3.11), and with a lupus anticoagulant was 2.83 (95% CI, 0.83-9.64). All studies had important methodologic limitations and we judged the overall quality of the evidence as very low. Although a positive APLA test appears to predict an increased risk of recurrence in patients with a first VTE, the strength of this association is uncertain because the available evidence is of very low quality.