Background: Home parenteral nutrition (PN) has improved the survival of children with intestinal failure. Important complications include catheter-related thrombosis, occlusion, and infection. This study evaluated the efficacy and safety of prophylactic anticoagulation in the prevention of these complications. Methods: Medical records were retrospectively reviewed of all children (0-18 years) with PN between January 1994 and March 2007 in 1 tertiary center. After introduction of prophylactic low molecular weight heparin or vitamin K antagonists in March 2007, all patients were prospectively followed until March 2010. Results: In sum, 14 patients did not receive prophylaxis; 13 switched from no prophylaxis to prophylaxis in March 2007; and 5 directly received prophylaxis. Median age of PN onset was 4 months (range, 0.1-202) in the nonprophylaxis group (n = 27) and 25 (range, 2-167) in the prophylaxis group (n = 18); 16 children received low molecular weight heparin and 2, vitamin K antagonists. Catheter-related thrombosis developed in 9 patients with no prophylaxis (33%) and 1 with prophylaxis (6%) (P =.034). Cumulative 5-year thrombosis-free survival was 48% and 93% in the nonprophylaxis and prophylaxis groups, respectively (P =.047). Per 1,000 PN days, the nonprophylaxis and prophylaxis groups had 2.6 and 0.1 occlusions (P =.04) and 4.6 and 2.1 infections (P =.06), respectively. Cumulative infection-free survival after 3 years was 19% and 46% in the nonprophylaxis and prophylaxis groups, respectively (P =.03). Bleeding complications did not occur. Conclusion: Thromboprophylaxis significantly decreased catheter-related thrombosis and occlusion in children with PN without complications. © 2012 American Society for Parenteral and Enteral Nutrition.