Background and objectives There are a limited number of publications on the features of arteriovenous graft infection in hemodialysis patients. The authors compared the clinical presentation, complications, and outcomes of infections of thigh and upper extremity grafts. Design, setting, participants, and measurements The authors queried a prospective access database at a large university medical center and identified 132 patients with graft infections (40 in the thigh and 92 in the upper extremity) requiring surgical excision. The authors collected information regarding the microbiology, complications, and clinical outcomes. Results The two graft groups were similar in age, gender, race, and frequency of diabetes. The median age of infected grafts was 162 days for thigh grafts versus 168 days for upper extremity grafts (P = 0.35). Thigh graft infections were more likely than upper extremity graft infections to be caused by a Gram-negative rod (31% versus 4%; P = 0.003), and more likely to result in a metastatic infection (15% versus 3%; P = 0.02). The duration of hospitalization associated with graft infection was similar (10.8 ± 5.4 versus 8.7 ± 6.3 days; P = 0.09). Finally, median catheter dependence was longer after thigh graft than upper arm graft infections (319 versus 237 days; P = 0.04). Conclusions As compared with upper extremity graft infections, thigh graft infections requiring excision are more likely to be caused by Gram-negative bacteria and to result in serious metastatic complications. These differences may require different empiric antibiotics and a higher index of suspicion for infection in hemodialysis patients with thigh grafts. © 2011 by the American Society of Nephrology.