Fibroblastic polyps of the colon and intestinal perineuriomas are unusual mucosal lesions with identical clinical and histologic features, and apparent different immunohistochemical and ultrastructural characteristics. However, immunohistochemical distinction was solely based on the results obtained with epithelial membrane antigen (EMA), an antibody whose reactivity on perineuriomas is difficult to demonstrate. Likewise, accurate ultrastructural diagnosis may be flawed by sampling error, preservation artifacts, or paucity of specific diagnostic features. In a recent short communication, it was suggested that both lesions may represent the same entity. To further evaluate this hypothesis, 28 colorectal polyps with clinical and histologic features of colonic fibroblastic polyps/perineuriomas (including 10 cases previously reported as fibroblastic polyps) were stained immunohistochemically for 4 markers of perineurial differentiation, that is, claudin-1, GLUT-1, collagen type IV, and EMA (the latter performed using an extended protocol for antigen retrieval and a kit for signal amplification). In addition, electron microscopy was performed in 4 cases. EMA and claudin-1 stained 26 of 28 (93%) polyps whereas GLUT-1 and collagen type IV were expressed in all of them. EMA reactivity was mostly focal and weak whereas the other markers displayed a diffuse and strong signal. Ultrastructural examination revealed elongated cells with features of perineurial differentiation including long, slender cytoplasmic processes with pinocytotic vesicles and an external lamina. Our findings support the hypothesis that fibroblastic polyps and perineuriomas of the colon represent the same entity. We suggest reclassifying fibroblastic polyps reactive to perineurial markers as perineuriomas. To reach an accurate diagnosis, we recommend employing at least 2 markers of perineurial differentiation, and performing EMA immunostaining with high antibody concentration, prolonged incubation time, and/or extended protocol for antigen retrieval.