Lymphocytic colitis, previously termed "microscopic colitis", is a clinicopathologic syndrome of watery diarrhea, grossly normal colonoscopy, and mucosal inflammatory changes. Since lymphocytic colitis is a new, incompletely characterized entity, a histopathologic study was performed to compare lymphocytic colitis (n = 16), collagenous colitis (n = 17), idiopathic inflammatory bowel disease (n = 16), acute colitis (n = 16), and histologically normal colon (n = 12). The study was a blinded semiquantitative analysis of histologic features in the surface epithelium, lamina propria, and crypts. The most distinctive feature of lymphocytic colitis was increased intraepithelial lymphocytes, particularly in the surface epithelium (P = .0001 v idiopathic inflammatory bowel disease, acute colitis, and normal colon). Other prominent features of lymphocytic colitis included surface epithelial damage (P less than .005 v idiopathic inflammatory bowel disease and normal colon), increased lamina propria chronic inflammation (P less than .01 v normal), and minimal crypt distortion or active cryptitis. There were striking similarities between lymphocytic colitis and collagenous colitis, but subepithelial collagen thickening was seen only in collagenous colitis. Idiopathic inflammatory bowel disease showed prominent crypt distortion and greater active inflammation, in addition to minimal intraepithelial lymphocytes. Acute colitis occasionally demonstrated prominent surface epithelial damage, but was otherwise dissimilar from lymphocytic colitis. We reached the following conclusions: (1) the entity "microscopic colitis" shows characteristic histopathology including prominent lymphocytic infiltration of epithelium, and thus, a more appropriate designation is lymphocytic colitis; (2) although lymphocytic colitis closely resembles collagenous colitis, each entity is distinct on biopsy; and (3) lymphocytic colitis is readily distinguishable from idiopathic inflammatory bowel disease, acute forms of colitis, and normal colorectum.