BACKGROUND In recent years, two new narrow-band imaging (NBI) classifications have been proposed: The NBI international colorectal endoscopic (NICE) classification and Japanese NBI expert team (JNET) classification. Most validation studies of the two new NBI classifications were conducted in classification setting units by experienced endoscopists, and the application of use in different centers among endoscopists with different endoscopy skills remains unknown. AIM To evaluate clinical application and possible problems of NICE and JNET classification for the differential diagnosis of colorectal cancer and precancerous lesions. METHODS Six endoscopists with varying levels of experience participated in this study. Eighty-seven consecutive patients with a total of 125 lesions were photographed during non-magnifying conventional white-light colonoscopy, non-magnifying NBI, and magnifying NBI. The three groups of endoscopic pictures of each lesion were evaluated by the six endoscopists in randomized order using the NICE and JENT classifications separately. Then we calculated the six endoscopists' sensitivity, specificity, accuracy, positive predictive value, and negative predictive value for each category of the two classifications. RESULTS The sensitivity, specificity, and accuracy of JNET classification type 1 and 3 were similar to NICE classification type 1 and 3 in both the highly experienced endoscopist (HEE) and less-experienced endoscopist (LEE) groups. The specificity of JNET classification type 1 and 3 and NICE classification type 3 in both the HEE and LEE groups was > 95%, and the overall interobserver agreement was good in both groups. The sensitivity of NICE classification type 3 lesions for diagnosis of SM-d carcinoma in the HEE group was significantly superior to that in the LEE group (91.7% vs 83.3%; P = 0.042). The sensitivity of JNET classification type 2B lesions for the diagnosis of high-grade dysplasia or superficial submucosal invasive carcinoma in the HEE and LEE groups was 53.8% and 51.3%, respectively. Compared with other types of JNET classification, the diagnostic ability of type 2B was the weakest. CONCLUSION The treatment strategy of the two classification type 1 and 3 lesions can be based on the results of endoscopic examination. JNET type 2B lesions need further examination.