Fundic gland polyps are benign lesions, composed of a disorderly arrangement of normal gastric corpus cell types, that occur in a large proportion of patients with familial adenomatous polyposis (FAP) but also develop sporadically in non-FAP patients as well. In this study, the authors evaluated and compared the endoscopic, histological, mucin histochemical, and microscopic stereologic features of 77 fundic gland polyps (FGPs) (15 FAP; 62 non-FAP) to determine if FAP-associated and sporadic lesions are histologically distinct. The authors also analyzed the distribution of mitotically active cells and smooth muscle cells in these lesions using MIB-1 and smooth muscle alpha-actin immunohistochemistry in an effort to determine the pathogenesis of these lesions. The results show that, compared with non-FAP cases, FAP patients with FGPs have a lower male-to-female ratio, a younger mean age at diagnosis, and a higher proportion of cases with multiple polyps. However, no differences were detected between FAP and non-FAP-associated FGPs with respect to any endoscopic, morphological, mucin histochemical, or stereometric features. Eighty-six percent of FGPs showed an increase in smooth muscle content, often in a pericystic distribution. MIB-1-positive proliferative cells were observed not only in the foveolar stem cell region, as expected, but also in the epithelium lining the microcysts and in the gland buds located directly adjacent to the microcysts. The authors conclude that FAP and non-FAP-associated FGPs are histologically identical, and propose that proliferation and subsequent differentiation of aberrantly located proliferative cells in these lesions may explain the histogenesis of FGPs.