Description: Purpose The American Joint Committee on Cancer (AJCC) staging manual has introduced a TNM staging classification for jejunal-ileal (midgut) neuroendocrine tumors (NETs). This classification has not been validated in a population consisting solely of midgut NETs. The purpose of this study was to test the prognostic validity of the classification in such a population. Methods Patients with jejunal and ileocecal NETs who were treated at the Moffitt Cancer Center between 2000 and 2010 were assigned stages (I through IV). Kaplan-Meier analyses for overall survival (OS) were performed on the basis of TNM stage and pathologic grade. Multivariate modeling was performed using Cox proportional hazards regression. Results We identified 691 patients with jejunal-ileocecal NETs. The AJCC classification in aggregate was highly prognostic for OS ( P 〈 .001). Five-year OS rates for stages I through IV were 100%, 100%, 91%, and 72%, respectively. The survival difference between stages III and IV was significant ( P 〈 .001); the difference between stages I/II versus III was not statistically significant ( P = .1). Among patients with stage IIIB tumors, 5-year survival rates were 95% for resectable tumors versus 78% for unresectable mesenteric tumors ( P = .02). A proliferative threshold of five mitoses per 10 high-power fields (HPF) was of greater prognostic value than a threshold of two mitoses per 10 HPF for discriminating between low- and intermediate-grade tumors. Conclusion Stage I and II midgut NETs are associated with identical survival rates. Stage IIIB tumors are heterogeneous, with significant differences in survival observed between resectable mesenteric lymph nodes versus unresectable masses in the root of the mesentery. A higher mitotic cutoff of five per 10 HPF may lead to improved prognostic differentiation between low- and intermediate-grade tumors. Revisions to the current AJCC staging and grading classification may be warranted.