Conventional colonoscopy misses some neoplastic lesions. We compared the sensitivity of chromoendoscopy and colonoscopy with intensive inspection for detecting adenomatous polyps missed by conventional colonoscopy. Fifty subjects with a history of colorectal cancer or adenomas underwent tandem colonoscopies at one of five centers of the Great Lakes New England Clinical Epidemiology and Validation Center of the Early Detection Research Network. The first exam was a conventional colonoscopy with removal of all visualized polyps. The second exam was randomly assigned as either pan-colonic indigocarmine chromoendoscopy or standard colonoscopy with intensive inspection lasting >20 minutes. Size, histology, and numbers of polyps detected on each exam were recorded. Twenty-seven subjects were randomized to a second exam with chromoendoscopy and 23 underwent intensive inspection. Forty adenomas were identified on the first standard colonoscopies. The second colonoscopies detected 24 additional adenomas: 19 were found using chromoendoscopy and 5 were found using intensive inspection. Chromoendoscopy found additional adenomas in more subjects than did intensive inspection (44% versus 17%) and identified significantly more missed adenomas per subject (0.7 versus 0.2, P < 0.01). Adenomas detected with chromoendoscopy were significantly smaller (mean size 2.66 +/- 0.97 mm) and were more often right-sided. Chromoendoscopy was associated with more normal tissue biopsies and longer procedure times than intensive inspection. After controlling for procedure time, chromoendoscopy detected more adenomas and hyperplastic polyps compared with colonoscopy using intensive inspection alone. Chromoendoscopy detected more polyps missed by standard colonoscopy than did intensive inspection. The clinical significance of these small missed lesions warrants further study.