The clinical significance of adenomyomatosis of the gallbladder remains unclear. This study aimed to clarify the relationship between segmental adenomyomatosis and gallbladder carcinoma, and to elucidate the histogenesis of gallbladder carcinoma associated with segmental adenomyomatosis. A total of 4,560 consecutive patients underwent cholecystectomy. The specimens were examined grossly and histologically. Adenomyomatosis of the gallbladder was divided into segmental, fundal, and diffuse types. Sixty noncancerous gallbladders with segmental adenomyomatosis were examined for epithelial metaplasia. The incidence of gallbladder carcinoma was higher in patients with segmental adenomyomatosis (22/334, 6.6%) than in those without (181/4226, 4.3%; P=0.049). This difference was more marked among patients equal to or older than 60 years of age (15/96,15.6% versus 147/2407, 6.1%, respectively; P<0.001). The other types of adenomyomatosis did not show any significant increases in the incidence of gallbladder carcinoma. In all 22 patients with both segmental adenomyomatosis and carcinoma, the tumors developed only in the fundal mucosa. Epithelial metaplasia was more marked in the fundal mucosa of segmental adenomyomatosis than in the neck mucosa (P=0.003). Segmental adenomyomatosis is a high-risk condition for gallbladder carcinoma, especially in elderly patients. Epithelial metaplasia appears to be related to increased carcinogenesis in the fundal mucosa of segmental adenomyomatosis.