INTRODUCTION: Pharmacologic prophylaxis (PP) is recommended for patients undergoing general surgical procedures with at least moderate risk of venous thromboembolism (VTE). The role of PP in patients undergoing hepatectomy is controversial, however, due to concerns regarding postoperative liver dysfunction and bleeding. METHODS: We conducted a retrospective analysis of a prospectively maintained institutional database in order to clarify the relationship between PP, postoperative INR, and risk of VTE. RESULTS: Postoperative VTE occurred in 55 of 2,147 patients (2.6 %) and was independently associated with advanced age, higher BMI, longer procedure time, and development of a major complication, as well as higher postoperative INR (≥1.5 versus <1.5: OR 2.50, P = 0.006). Patients undergoing more extensive liver resection with higher postoperative INR were less likely to receive PP, but receipt of PP demonstrated no relationship with either VTE incidence or hemorrhagic complications. CONCLUSIONS: In this large single-institution study, incidence of VTE was not associated with PP but was associated with higher postoperative INR, contrary to the notion that postoperative liver dysfunction is protective against VTE. The interplay between prothrombotic and antithrombotic mechanisms in posthepatectomy patients must be more completely characterized before broad recommendations can be made regarding PP use in these patients.