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Objectives: To evaluate the yield and clinical impact of random biopsies taken during colonoscopic surveillance of patients with longstanding ulcerative colitis (UC)., Methods: Retrospective analysis of 1,010 colonoscopies performed from 1998 to 2008. Colonoscopy and pathology reports were reviewed to assess the yield and clinical impact of random biopsies. In total, 475 patients with UC who underwent colonoscopy at the Academic Medical Centre Amsterdam were included in this study. The main outcome measures are neoplasia yield per-colonoscopy and clinical impact per-patient of random biopsies., Results: Of all colonoscopies, 466 were performed for surveillance (in 167 patients) during which 11,772 random biopsies were taken (median 29). Overall, neoplasia was detected in 88 colonoscopies (53 patients): in 75 colonoscopies (85%) by targeted biopsies only and in 8 (9.1%) by both targeted and random biopsies. Neoplasia was detected in random biopsies only in five (5.7%) colonoscopies in four (7.5%) patients. Two of these four patients with neoplasia detected only by random biopsies had visible neoplasia in previous colonoscopies. One patient had unifocal low-grade intraepithelial neoplasia (LGIN) that could not be confirmed in three subsequent colonoscopies. The last patient had multifocal LGIN and suspicious appearing ulcerations. Proctocolectomy confirmed the presence of neoplasia., Conclusions: The yield of random biopsies is low whereas UC-associated neoplasia is macroscopically visible in 94% of colonoscopies. During 10-year surveillance, neoplasia was detected in only random biopsies in four patients of whom only one had clinical consequences. The low yield and lack of clinical consequences from random biopsies in this high-risk population raise questions about the necessity and cost-effectiveness of their routine use during UC surveillance.