Objective To determine the incidence of major adverse events related to a large volume of image-guided liver biopsies performed at our institution over a 12-year period and to identify risk factors for major bleeding events. Patients and Methods A retrospective analysis of an internally maintained biopsy registry was performed. The analysis revealed that 6613 image-guided liver biopsies were performed in 5987 adult patients between December 7, 2001, and December 31, 2013. Liver biopsies were performed using real-time ultrasound guidance and a spring-loaded biopsy device, with rare exceptions. Adverse events considered major and included in this study were hematoma, infection, pneumothorax, hemothorax, and death. Using data from the biopsy registry, we evaluated statistically significant risk factors (P<.05) for hematoma related to image-guided liver biopsy, including coagulation status, biopsy technique, and medications. Results A total of 49 acute and delayed major adverse events (0.7%) occurred after 6613 liver biopsy events. The incidence of hematoma requiring transfusion and/or angiographic intervention was 0.5% (34 of 6613). The incidence of infection was 0.1% (8 of 6613), and that of hemothorax was 0.06% (4 of 6613). No patient (0%) incurred a pneumothorax after biopsy. Three patients (0.05%) died within 30 days of liver biopsy, 1 being directly related to biopsy. Thirty-eight of 46 major adverse events (83%) presented acutely (within 24 hours). More than 2 biopsy passes, platelets 50,000/μL or less, and female sex were statistically significant risk factors for postbiopsy hemorrhage. Conclusion Image-guided liver biopsy performed by subspecialized interventionalists at a tertiary medical center is safe when the platelet count is greater than 50,000/μL. With appreciation of specific risk factors, safety outcomes of this procedure can be optimized in both general and specialized centers.