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Background: Aim. The aim of this study was to investigate biological resistance to enoxaparin and rebound effect after prophylaxis withdrawal, using thrombin generation (TG) assay., Methods: Fifteen-patients undergoing femoro-popliteal bypass grafting (enoxaparin 4000 antiXaIU+75 mg clopidogrel), and 15-patients undergoing total-hip-replacement (THR) (enoxaparin alone). TG-assay parameters (lag-time, endogenous-thrombin-potential, peak-, time-to-peak, and Mean-Rate-Index) were assessed to investigate heparin resistance and rebound effect after prophylaxis interruption. Measurements were obtained preoperative, postoperative (before prophylaxis initiation), 8-days postoperative, and 48-hours after anticoagulant withdrawal (day 32)., Results: Surgery increased TG in vascular-patients despite intra-operative unfractioned heparin administration when compared to orthopedic patients (MRI:P=0.039, ETP:P=0.001, PGT:P=0.003), but this perioperative prothrombotic status was reversed by postoperative thromboprophylaxis. No thromboembolic events were observed. Similar TG parameter values between the 8th and 32nd postoperative day indicate that vascular patients were adequately protected after prophylaxis withdrawal, probably due to the synergic action of clopidogrel, while orthopedic patients increased TG on day-32 compared to the 8th postoperative day (P=0.03, for both lag-time and ttPeak). Furthermore, on day-32, a prothrombotic status (increased TG) was observed in the orthopedic patients (P=0.034, and 0.004 for ttPeak and lag-time, respectively). Inter-individual variability to enoxaparin response was observed in both groups:7/15 vascular and 10/15 orthopedic patients increased TG despite anticoagulant administration, which reveals heparin-resistance. Among the heparin-resistant patients, 4 vascular and 6 orthopedic increased TG after anticoagulant withdrawal, depicting a rebound effect to activation of coagulation., Conclusions: Heparin-resistance is not a rare phenomenon in clinical practice and was found in about half of our patients. A rebound effect of coagulation activation after thromboprophylaxis withdrawal is observed in the extended postoperative period. This phenomenon is attenuated with the addition of concomitant antiplatelet (clopidogrel) treatment.