BACKGROUND AND STUDY AIM: Valid tissue sampling of colorectal adenomas is crucial for their management in terms of treatment and follow-up. The aim of this study was to assess the validity of a cold biopsy sample as representative for the whole polypectomy specimen, with regard to histopathological features. PATIENTS AND METHODS: As part of the Norwegian Colorectal Cancer Prevention trial, 442 participants (60% men) who fulfilled the criterion of colonoscopic recovery of adenoma that had been biopsied at flexible sigmoidoscopy, had their adenomas subsequently removed by polypectomy (snare resection) at colonoscopy. Logistic regression analysis was used to determine which variables contributed to the histopathological discrepancy between cold biopsy and polypectomy specimens. RESULTS: Among the 532 colorectal adenomas biopsied at flexible sigmoidoscopy and removed by colonoscopy, the assessment of intraepithelial neoplasia (dysplasia) status was changed in 51 adenomas (10%), and 38 (7%) of them had been underestimated at biopsy compared with polypectomy. Likewise, the assessment of villousness was changed in 45 adenomas (9%), being upgraded in 26 (6%) at polypectomy compared with biopsy. In a multivariate model, the diameter of neoplasia at polypectomy was positively associated with increased risk of the underestimation of intraepithelial neoplasia and/or villousness influencing a diagnosis of advanced colorectal neoplasia, when cold biopsy and polypectomy specimens were compared ( Ptrend=0.01). Among 56 cases of advanced neoplasia, 35 (63%) showed only low-grade intraepithelial neoplasia on biopsy. CONCLUSIONS: Biopsy-based diagnosis underestimated histopathological diagnosis in about 10% of colorectal adenomas detected by flexible sigmoidoscopy screening, but advanced neoplasia was underestimated in more than 60%. Efforts must be made to obtain polypectomy specimens to secure precise diagnosis.