Background and study aims: The resolution of endoscopes has increased in recent years. Modern Fujinon colonoscopes have a charge-coupled device (CCD) pixel density of 650000 pixels compared with the 410000 pixel CCD in standard-definition scopes. Acquiring high-definition scopes represents a significant capital investment and their clinical value remains uncertain. The aim of the current study was to investigate the impact of high-definition endoscopes on the in vivo histology prediction of colonic polyps. Patients and methods: Colonoscopy procedures were performed using Fujinon colonoscopes and EPX-4400 processor. Procedures were randomized to be performed using either a standard-definition EC-530 colonoscope or high-definition EC-530 and EC-590 colonoscopes. Polyps of < 10 mm were assessed using both white light imaging (WLI) and flexible spectral imaging color enhancement (FICE), and the predicted diagnosis was recorded. Polyps were removed and sent for histological analysis by a pathologist who was blinded to the endoscopic diagnosis. The predicted diagnosis was compared with the histology to calculate the accuracy, sensitivity, and specificity of in vivo assessment using either standard- or high-definition scopes. Results: A total of 293 polyps of < 10 mm were examined - 150 polyps using the standard-definition colonoscope and 143 polyps using high-definition colonoscopes. There was no difference in sensitivity, specificity or accuracy between the two scopes when WLI was used (standard vs. high: accuracy 70 % [95 %CI 62 - 77] vs. 73 % [95 %CI 65 - 80]; P = 0.61). When FICE was used, high-definition colonoscopes showed a sensitivity of 93 % compared with 83 % for standard-definition colonoscopes (P = 0.048); specificity was 81 % and 82 %, respectively. Conclusions: There was no difference between high- and standard-definition colonoscopes when white light was used, but FICE significantly improved the in vivo diagnosis of small polyps when high-definition scopes were used compared with standard definition.