The morphology of gastric hamartomatous polyps from patients with juvenile polyposis syndrome (JuvPS) and Peutz-Jeghers' Syndrome (PJS) is poorly characterized. We investigated the histologic features of gastric polyps in patients with established JuvPS or PJS to develop improved histologic criteria to distinguish these from gastric hyperplastic (HP) polyps. The patients with clinically confirmed hamartomatous polyposis syndromes were identified, including 26 patients with JuvPS (both familial and sporadic) and 17 patients with PJS. All gastric polyps (n=30) from these patients were intermixed with gastric HP polyps from nonsyndromic patients (n=26) and subsequently blindly reviewed by a panel of gastrointestinal pathologists. A consensus diagnosis was rendered. The panel then reviewed the slides in the context of clinical data and identified histologic features for distinguishing JuvPS, PJS, and HP gastric polyps based on epithelial changes, pit architecture, lamina propria features, and smooth muscle qualities. A sleeping period of 6 months lapsed before the same cases were renumbered and blindly rereviewed independently. Diagnoses were then rendered while adhering to the suggested criteria. Cases that the reviewers recalled were discarded from the study (n=8). On initial review, accuracy in diagnosis of gastric polyps in JuvPS was 50% and was 18% in PJS compared with 92% for HP gastric polyps. Adherence to the recommended histologic criteria resulted in diagnostic accuracy of 41% for JuvPS and 54% for PJS, compared with 73% for HP gastric polyps. Accuracy in diagnosis in antral mucosa was 66%, oxyntic mucosa 71%, and transitional-type mucosa (mixed antral and oxyntic) 32%. The diagnostic accuracy based on polyp size was 59% for polyps which were less than equal to 3 mm, 56% for those 4 to 9 mm, and 81% for polyps which were more than equal to 10 mm. The identification of gastric polyps from JuvPS and PJS patients without the context of clinical history of these syndromes remains poor, even with adherence to a set of morphologic criteria. Abiding by such criteria improved recognition of PJS polyps by more than double (P<0.19), but yielded an accuracy of only 54%. The accuracy did not improve when results were stratified for polyp location but did with biopsy size which were more than equal to10 mm. Whereas these syndromic polyps are readily diagnosed in the small bowel and colon, histologic features to distinguish gastric JuvPS and PJS from gastric HP polyps are unreliable.