BACKGROUND: Thromboprophylaxis extended after hospital discharge in medically ill patients currently is not recommended by practice guidelines because of uncertainty about the benefit for preventing major or fatal thromboembolic events, and the risk of bleeding. METHODS AND RESULTS: We assessed the benefit and risk of thromboprophylaxis with rivaroxaban 10 mg once daily extended for 25 to 45 days after hospitalization for preventing major thromboembolism in medically ill patients using the pooled data in 16 496 patients from 2 randomized trials, MARINER (Medically Ill Patient Assessment of Rivaroxaban Versus Placebo in Reducing Post-Discharge Venous Thrombo-Embolism Risk) and MAGELLAN (Multicenter, randomized, parallel-group efficacy and safety study for the prevention of venous thromboembolism in hospitalized medically ill patients comparing rivaroxaban with enoxaparin). The data from the MARINER trial were pooled with the data from the MAGELLAN trial in patients who were free of thrombotic or bleeding events up to the last dose of enoxaparin/placebo and who continued in the outpatient phase of thromboprophylaxis. The composite outcome of major thromboembolic events (symptomatic deep vein thrombosis, nonfatal pulmonary embolism, myocardial infarction, and nonhemorrhagic stroke) and all-cause mortality was used to assess benefit and was compared with the risk of the composite of fatal and critical site bleeding. The incidence of the composite efficacy outcome was 1.80% (148 of 8222 patients) in the rivaroxaban group, compared with 2.31% (191 of 8274 patients in the placebo group) (HR, 0.78 [95% CI, 0.63-0.97], P=0.024). Fatal or critical site bleeding events were infrequent and occurred in <0.1% of patients in both groups (rivaroxaban 0.09%; placebo 0.04%; HR, 2.36; P=0.214). CONCLUSIONS: The results suggest a benefit for reducing major thromboembolic outcomes (number needed to treat: 197), with a favorable trade-off to fatal or critical site bleeding (number needed to harm: 2045).