Solitary rectal ulcer syndrome (SRUS) is sufficiently uncommon that the clinician or general pathologist may lack familiarity with the disorder and may confuse it with other inflammatory bowel diseases. To evaluate the role of collagen staining in facilitating the differential diagnosis of SRUS, an initial open review was undertaken on 1672 consecutive patients whose 4780 colorectal biopsies were stained with H&E with added saffron to demonstrate collagen. Excess mucosal collagen was present in 39 (2.3%) of these patients. Twenty patients with a diffuse excess of mucosal collagen in biopsies from rectal ulcer margins or from otherwise abnormal rectal mucosa had SRUS; in the remaining 19 patients, excess mucosal collagen was focal (seven ischemic colitis, five collagenous colitis, three adenocarcinoma, and four chronic idiopathic ulcerative colitis). Diffuse excess mucosal collagen never was seen in idiopathic inflammatory bowel disease (128 Crohn's colitis and 446 ulcerative colitis). Blinded reviews then were performed on rectal biopsies from 33 patients with a variety of diagnoses (14 SRUS and 19 controls). Diffuse excess collagen by saffron staining was consistently observed in SRUS but was absent in all 19 controls. Additional blinded reviews were carried out because the collagen staining pattern in ischemic colitis, although focal, could potentially be confused with SRUS. It was possible to differentiate these two diseases blindly from one another by using additional histologic criteria (14 SRUS and 12 ischemic colitis). We conclude that the demonstration of a diffuse excess of mucosal collagen in rectal biopsies facilitates the diagnosis of SRUS and differentiates it from idiopathic ulcerative colitis and Crohn's disease, with which SRUS is often confused, and other inflammatory bowel diseases.