We report a case of neuronal hypertrophy associated with acute appendicitis in which significant neuronal fibers and the number of ganglion cells increased in the absence of inflammatory cells. Differential diagnosis from diffuse ganglioneuromatosis by the pathologic findings of resected specimen was difficult. A 33-year-old Japanese female visited our hospital complaining of acute abdominal pain. The patient underwent appendectomy upon the diagnosis of acute appendicitis on the day of admission. Postoperative examinations found no neoplastic lesions in other organs or inherited disorders such as multiple endocrine neoplasia (MEN) type 2b and von Recklinghausen's disease (VRD). The pathologic diagnosis was neuronal hypertrophy of the appendix. Because the clinical outcomes of diffuse ganglioneuromatosis and neuronal hypertrophy of the gastrointestinal tract are quite different, clinical and pathologic examination should be carefully carried out for lesions in which significant proliferation of neuronal components is seen.