We conducted a retrospective clinicopathologic and immunohistochemical study of the biologic significance of mesoappendix infiltration in 15 appendiceal neuroendocrine tumors selected from a series of 42 primary tumors. In all cases, the tumor was found incidentally and measured less than 2 cm (mean, 0.84 cm). In 13 cases, it was located in the tip of the appendix and in the midportion in 2. Histologically, none showed relationship with overlying mucosa. Necrosis was absent; mitotic figures were rare. The Ki-67 labeling index was low (1%-2%). In all cases, S-100 protein immunostaining disclosed positive elements with cytoplasmic dendritic processes closely intermingled with neuroendocrine neoplastic cells. All patients (8 males; 7 females; mean age, 38.2 years) underwent simple appendectomy. A right-sided hemicolectomy was performed subsequently in 1 case. After a mean follow-up of 52.6 months (range, 8-143 months), none had died of disease or had recurrent or metastatic disease. Our results confirm that appendiceal neuroendocrine tumors seem to have a different phenotype from those occurring in other gastrointestinal sites. Tumors less than 2 cm, even with mesoappendiceal infiltration, have an excellent prognosis, and simple appendectomy seems to be the appropriate therapeutic approach.