Reduced clot permeability and lysability have been reported in patients who experienced venous thromboembolism (VTE) following lower limb injury despite pharmacological thromboprophylaxis. We hypothesized that similarly altered fibrin clot properties characterize patients with post-discharge VTE despite thromboprophylaxis during prior hospitalization due to acute medical illnesses.In a case-control study, we assessed 48 patients who developed VTE within 4 weeks post-discharge despite pharmacological thromboprophylaxis during hospitalization (the thromboprophylaxis group) and three age- and sex-matched control groups (n = 48 each): (1) patients who developed VTE following hospitalization without pharmacological thromboprophylaxis (the no-thromboprophylaxis group), (2) patients with unprovoked VTE and (3) individuals without history of VTE (the no-VTE group). Blood samples were obtained following ≥3 months of anticoagulation in VTE patients. Fibrin clot properties, thrombin generation and fibrinolysis activators and inhibitors were assessed.Compared with the no-VTE group, the thromboprophylaxis group formed denser fibrin networks reflected by lower clot permeability (K, -13%) and impaired fibrinolysis, as evidenced by prolonged clot lysis time (CLT, +14%) and lower rate of D-dimer release from clots (D-D, -9%) accompanied by elevated high-sensitivity C-reactive protein (hsCRP, +79%), peak thrombin generation (+55%) and α-antiplasmin (+10%, all p < 0.05). Similar fibrin clot features were observed following unprovoked VTE. The thromboprophylaxis group had also lower K (-13%), elevated α-antiplasmin (+18%) and higher peak thrombin generation (+25%, all p < 0.05) as compared with the no-thromboprophylaxis group.Unfavorably altered plasma clot properties and increased thrombin generation characterize medical patients with post-discharge VTE despite receiving pharmacological thromboprophylaxis during hospitalization for acute conditions.