OBJECTIVE The accuracy of conventional colonoscopy to differentiate neoplastic and non-neoplastic polyps is limited, justifying a biopsy for histologic analysis. Magnifying chromocolonoscopy has emerged as the best tool available for differentiating adenomatous and hyperplastic polyps during colonoscopy; however, magnifying endoscopes are rarely used in endoscopy units. This study aimed to further validate the effectiveness of magnifying chromocolonoscopy in the diagnosis of neoplastic colorectal polyps in a screening center. METHODS Five hundred average-risk subjects were randomly divided into two groups: a magnifying chromocolonoscopy group and a conventional chromocolonoscopy group, each of 250 subjects. Lesions were analyzed according to Kudo's classification of pit pattern (types I-V) and additionally subdivided into non-neoplastic (types I-II) and neoplastic (types III-V). Lesions judged as neoplastic were resected and those judged as non-neoplastic were left in situ. Only lesions < or =10 mm were included in the study. Resected lesions were analyzed with histopathological examination. RESULTS The overall accuracy of magnifying chromocolonoscopy for differentiating neoplastic lesions (95%, 135 of 142), was significantly higher than that of conventional chromocolonoscopy (84%, 102 of 122; P < 0.01). The accuracy of magnifying chromocolonoscopy for differentiating neoplastic lesions < or =5 mm was 94% (135 of 142), whereas that of conventional chromocolonoscopy was only 78% (69 of 89; P < 0.001). Results were not affected by the macroscopic types. CONCLUSIONS Magnifying chromocolonoscopy is superior to conventional chromocolonoscopy for the diagnosis of colorectal neoplastic lesions in the setting of a health testing center.