AIMS: Endoscopic biopsy diagnosis of Crohn's disease (CD) is problematic due to lack of specific microscopic features and patchy involvement. There is no documentation of the pattern and severity of microscopic features of CD at initial presentation in adults or children. We aimed to assess the initial mucosal biopsy features of CD in adults and to identify any specific features to confirm the diagnosis. METHODS: Thirty sets of initial, adult endoscopic biopsies suspected to be CD with subsequent resections, repeat biopsies with long-term follow-up, and/or other confirmatory laboratory results were analysed by three gastrointestinal pathologists, blinded for the final diagnosis for mucosal architectural changes, epithelial abnormalities, chronic and active inflammation and changes of muscularis mucosae and submucosa. There were 25 cases of CD and five cases of non-CD for comparison (3 tuberculosis and 2 right-sided diverticular disease and associated colitis). Cases confirmed as ulcerative colitis were excluded, as diagnostic challenges are already well established. RESULTS: The majority of initial biopsies (96%) of CD were abnormal with active chronic ileocolitis with a very high proportion (80%) showing the classic combination of abnormal mucosal architecture, epithelial abnormalities and active chronic inflammation. The most sensitive feature was lamina proprial chronic inflammation (sensitivity 92.7%). Sensitivity for other features was as follows: active inflammation 87.8%, basal plasmacytosis 82.1%, architectural changes 80.5% and epithelial abnormalities 70.7%. Abnormalities were found in 94% of ileal and 76% of colonic biopsies. No feature was specific as all tuberculosis and diverticular disease cases showed the classic combination. Granulomata were seen in 10 of 41 CD, in all five tuberculosis and in no diverticular disease biopsies. Small, tight, well defined granulomata characterised CD over large coalesced ganulomata of tuberculosis. Paneth cell and pseudopyloric metaplasia was seen only in CD (2/25). CONCLUSIONS: Initial endoscopic biopsies of adult CD are significantly abnormal and a majority shows active chronic ileocolitis. The features are sufficiently important to suspect CD at initial presentation in the appropriate clinical setting. Tuberculosis and diverticular disease associated colitis are two important mimics to consider in addition to ulcerative colitis.