PTUI is an infrequently described and incompletely characterized complication of intestinal transplantation (ITx). Similarities to Crohn’s disease include localization to terminal ileum, risk for stricture, and response to biological and antimicrobial agents. Etiology of PTUI and impact on long-term graft function remain unclear. In order to gain insights into PTUI, we retrospectively studied patients receiving an ITx between 11/2003 and 12/2012 who survived at least 3-years. PTUI was found in 38 of 103 patients (37%) at a median interval of 1.6 (0.04-9.8) years after ITx. Presenting symptoms included diarrhea (34%), abdominal pain (32%), lower GI bleeding (14%), occult iron deficiency (10%), and fever (17%); half of the cohort had no symptoms. Potential risk factors for PTUI that were considered in the analysis included 1) recipient variables such as age, gender, liver disease, CMV status, NOD mutation status, and underlying disease, 2) donor factors such as type of ITx, D/R weight ratio, style of ileostomy construction and closure time, and operative and recovery times, and 3) immune factors such as results of cross-match, sensitization, HLA mismatching, and immunosuppressive induction. In univariable analysis, significant (p<0.05) predictors of PTUI included non-inclusion of graft colon/graft ICV (OR = 8.242, p=0.0001), Santulli ileostomy (OR=3.900, p= 0.005), age < 18 yr (OR=3.071, p=0.012), recipient NOD2 mutation (OR=2.860, p=0.030), shorter warm ischemia time (OR=0.985, p= 0.014), and longer hospital stay (OR=0.979, p=0.037). PTUI might also have been associated with reduced incidence of post-operative abscess (10.5% vs. 26.2%, p=0.057) and acute rejection occurring after 1-yr (26.3% vs. 12.3%, p=0.071) but not chronic rejection. PTUI did not affect 5-year graft survival, being 89% in those with PTUI and 81% in those without (p=0.168). This study suggests that absence of an ICV and the resulting increased contact of distal ileal graft mucosa with colonic succus and microflora are a key precipitant of PTUI and that the presence of NOD2 mutations promotes ileal injury in this setting. The high frequency of morbidities resulting from PTUI suggests that inclusion of graft colon with ICV should be considered in ITx whenever possible.