Peutz-Jeghers syndrome is an autosomal dominant condition characterized by gastrointestinal hamartomatous polyps. The pathologic identification of a Peutz-Jeghers polyp is integral to the diagnosis of this syndrome that often remains undiagnosed until after these polyps are identified. Histologically, Peutz-Jeghers polyps are characterized by a distinctive arborization of smooth muscle within the lamina propria. Colonic Peutz-Jeghers polyps, however, may mimic mucosal prolapse polyps or virtually any colonic polyp that undergoes prolapse. In this paper, we explore the morphological features of colonic Peutz-Jeghers polyps and the diagnostic challenges associated with these polyps. Colonic polyps from patients with Peutz-Jeghers syndrome were identified (n=34). The control cohort, included mucosal prolapse polyps (n=5), hyperplastic polyps (n=10) and tubular adenomas with prolapse (n=9), ganglioneuromatous polyps (n=2) and juvenile polyps (n=14). Intramucosal smooth muscle fibers were identified in all classes of polyps. Twenty-three of the 34 colonic Peutz-Jeghers polyps were characterized by lobulated clusters of colonic crypts. On immunohistochemistry, desmin-positive smooth muscle fibers were seen surrounding these lobules. This lobular organization of the crypts was not identified in mucosal prolapse polyps and hyperplastic polyps or tubular adenomas with prolapse; only one of the 14 juvenile polyps showed this pattern of reactivity on a desmin stain. Our data suggests that the histologic hallmark of colonic Peutz-Jeghers polyps is the lobular organization of the crypts, and that an arborizing pattern of smooth muscle proliferation is neither sensitive nor a specific marker of colonic Peutz-Jeghers polyps. The presence of desmin-positive smooth muscle fibers surrounding the lobules is a helpful diagnostic feature of colonic Peutz-Jeghers polyps, and facilitates the distinction of these polyps from non-Peutz-Jeghers polyps with prolapse-like changes.