Background and aims: Chronic intestinal failure (CIF) has been long-recognized, however the underlying etiology and risk factors have not been historically well-studied. We aim to study the underlying etiologies of CIF and predictive factors for long-term parenteral support (PS). Methods: We retrospectively identified patients with newly diagnosed CIF who received PS to maintain nutrition at the Cleveland Clinic between 2000 and 2017. Long-term PS was defined as a duration of more than 3 months. Univariable and multivariable logistic regression analyses were performed to identify the predictors of the need for long-term PS. Results: We identified 350 patients with CIF, 150 (43%) and 200 (57%) were diagnosed before and after 2010, respectively. The most common etiology was Crohn's disease (CD) in both cohorts (34.7% versus 30.5%, p = 0.41). Graft-versus-host-disease (GVHD) was a less frequent cause of CIF after 2010 (12.7% versus 2.5%, p = 0.0002). The type of PS was mostly total parenteral nutrition before and after 2010, 95% and 96%, respectively (p = 0.55). On univariable analysis, absence of ileocecal valve (p < 0.0001), ischemic bowel disease (p = 0.009), and whole colon resection (p = 0.033) were associated with the need for long-term PS. On multivariable analysis, absence of ileocecal valve (OR 2.19, p = 0.011) and ischemic bowel disease (OR 3.04, p = 0.003) remained statistically significant predictors of long-term PS. Conclusion: In our cohort of patients with CIF, CD remains the leading etiology over the last 20 years, whereas GVHD is less common after 2010. The absence of ileocecal valve and ischemic bowel disease were reliable predictive factors for requiring long-term PS.