We compared 315 patients with deep vein thrombosis who underwent major orthopedic surgery with 618 who underwent general surgery in a prospective registry of consecutive ultrasound-confirmed deep vein thrombosis patients. Orthopedic patients had fewer indwelling central venous catheters (14.0% vs. 46.4%, P < .0001) as well as lower rates of congestive heart failure (7.0% vs. 13.4%, P = .002), cancer (5.1% vs. 28.6%, P < .0001), and diabetes (7.0% vs. 12.6%, P = .004). Extremity discomfort (43.5% vs. 30.3%, P < .0001) and erythema (10.1% vs. 4.8%, P = .001) were more common in orthopedic patients, but dyspnea was less common (11.4% vs. 18.0%, P = .005). There was an increased use of graduated compression stockings (19.4% vs. 15.0%, P = .04), low-molecular-weight heparin (18.7% vs. 12.1%, P = .003), and warfarin (31.7% vs. 11.0%, P < .0001) for deep vein thrombosis prophylaxis in the orthopedic surgery group. Orthopedic surgical patients had a higher frequency of calf deep vein thrombosis than patients who underwent general surgery (38.4% vs. 2.1%, P < .0001). In both groups, 28% did not receive prophylaxis. In conclusion, despite having fewer comorbid conditions, orthopedic patients with deep vein thrombosis remain particularly vulnerable to calf deep vein thrombosis. Rates of venous thromboembolism prophylaxis were inadequate.