Extended- duration pharmacological thromboprophylaxis, for at least 28 days, is effective for the prevention of symptomatic venous thromboembolism (VTE) in high- risk surgical patients but is of uncertain benefit in hospitalized medical patients. We aimed to evaluate the efficacy and safety of extended- duration thromboprophylaxis in hospitalized medical patients. We conducted a systematic PubMed, Medline and EMBASE literature search until June 2016 and a meta- analysis of randomized controlled trials which compared extended- duration with short- duration thromboprophylaxis in hospitalized medical patients. Four randomized controlled trials comparing extendedduration prophylaxis (24- 47 days) with short- duration prophylaxis (6- 14 days) in a total of 34,068 acutely ill hospitalized medical patients were included. When compared with short- duration prophylaxis, extended- duration prophylaxis was associated with a decrease in symptomatic proximal or distal deep vein thrombosis (DVT) [relative risk (RR) = 0.52; 95% confidence interval (Cl): 0.35- 0.77: p = 0.001; absolute risk reduction (ARR) = 0.32%, number needed to treat (NNT) = 313], and symptomatic nonfatal pulmonary embolism (RR = 0.61; 95% Cl 0.38- 0.99: p = 0.04; ARR = 0.16%; NNT = 625), an increase in major bleeding (RR = 2.08; 95% Cl 1.50- 2.90: p < 0.0001, absolute risk increase = 0.41%, number needed to harm = 244), and no significant reduction in VTE- related mortality (RR = 0.69; 95% Cl 0.45- 1.06: p = 0.09) or all- cause mortality (RR = 1.00; 95% CI 0.89- 1.12; p = 0.95). There was heterogeneity for major bleeding due to results from the APEX trial (no difference between betrixaban and enoxaparin). Compared with short- duration thromboprophylaxis, extended- duration treatment reduces the risk for symptomatic DVT and non- fatal pulmonary embolism. Extended treatment with apixaban, enoxaparin and rivaroxaban but not betrixaban increases the risk for major bleeding.