BACKGROUND: Identifying previously undiagnosed cancer in patients with newly diagnosed venous thromboembolism (VTE) is important. Screening for malignant conditions can potentially diagnose more cases of cancer and at earlier stages, thereby preventing cancer-associated morbidity and perhaps mortality. PURPOSE: To summarize the period prevalence of previously undiagnosed cancer at baseline (within 1 month of VTE diagnosis), 6 months, and 12 months after VTE diagnosis and to quantify the additional value of an extensive cancer screening strategy (limited screening plus imaging techniques or tumor marker measurement) at baseline compared with more limited screening (history, physical examination, and simple widely available tests) at baseline. DATA SOURCES: MEDLINE, EMBASE, the Cochrane Register of Controlled Trials, and Evidence-Based Medicine Reviews. STUDY SELECTION: A total of 36 studies that reported the prevalence of undiagnosed cancer at baseline, 6 months, and 12 months were selected. Fourteen articles and 1 abstract also met inclusion criteria for the assessment of extensive versus limited cancer screening. DATA EXTRACTION: Two reviewers independently extracted data onto standardized forms. DATA SYNTHESIS: The period prevalence of previously undiagnosed cancer in patients with unprovoked VTE was 6.1% (95% CI, 5.0% to 7.1%) at baseline and 10.0% (CI, 8.6% to 11.3%) from baseline to 12 months. An extensive screening strategy using computed tomography of the abdomen and pelvis statistically significantly increased the proportion of previously undiagnosed cancer detected from 49.4% (CI, 40.2% to 58.5%) (with limited screening alone) to 69.7% (CI, 61.1% to 77.8%) in patients with unprovoked VTE. LIMITATION: The investigators could not determine complication rates, cost-effectiveness, and difference in morbidity and mortality associated with extensive screening strategies. CONCLUSION: Previously undiagnosed cancer is frequent in patients with unprovoked VTE. Many cases of previously undiagnosed cancer are missed by screening. An extensive cancer screening strategy detects more malignant conditions than does a limited screening strategy.