Intestinal failure (IF) is defined as the reduction of functional gut mass necessary to maintain health and growth in children. Causes of IF include short bowel syndrome (SBS), neuromuscular intestinal disorders (NID), and severe protracted diarrhea (SPD). If patients require long-term parenteral nutrition (PN); they can now be discharged on home PN (HPN), thus improving their quality of life. Children requiring long-term PN are at high risk of developing life-threatening IF complications that hinder HPN, namely, IF associated liver disease (IFALD), catheter-related infections (CRI), and thrombosis. The goal of our study was to retrospectively evaluate the prevalence of life-threatening complications among IF patients according to the HPN indication. From January 1989 to May 2006, 60 IF patients (41 boys and 19 girls) underwent prolonged HPN. Total program duration was 46,391 days (127 total years, mean 2.1 years per patient). Indications for HPN were SBS in 36 cases, SPD in 19 cases, or NID in 5 cases. In our experience patients affected by SBS displayed a significantly higher prevalence of life-threatening complications than patients with other IF causes. Sixteen (27%) among 60 patients developed IFALD. CRI and thrombosis prevalence were 1.4/1000 central venous catheter (CVC) days and 0.2/1000 CVC days respectively. SBS seemed to lead to life-threatening complications more often than other HPN indications. SBS patients on long-term PN therefore require careful management to identify complications early, and they seem to be the candidates for early referral to small bowel transplantation centers.