A second-generation capsule endoscopy system, using the PillCam Colon 2, was developed to increase sensitivity for colorectal polyp detection compared with the first-generation system. The performance of this new system is reported. In a five-center feasibility study, second-generation capsule endoscopy was prospectively compared with conventional colonoscopy as gold standard for the detection of colorectal polyps and other colonic disease, in a cohort of patients scheduled for colonoscopy and having known or suspected colonic disease. Colonoscopy was independently performed within 10 hours after capsule ingestion. Capsule-positive but colonoscopy-negative cases were counted as false-positive. 104 patients (mean age 49.8 years) were enrolled; data from 98 were analyzed. Patient rate for polyps of any size was 44 %, 53 % of these patients having adenomas. No adverse events related to either procedure were reported. The capsule sensitivity for the detection of patients with polyps >or= 6 mm was 89 % (95 % confidence interval CI 70 - 97) and for those with polyps >or= 10 mm it was 88 % (95 %CI 56 - 98), with specificities of 76 % (95 %CI 72 - 78) and 89 % (95 %CI 86 - 90), respectively. Both polyps missed by colonoscopy and mismatch in polyp size by study definition lowered specificity. Overall colon cleanliness for capsule endoscopy was adequate in 78 % of patients (95 %CI 68 - 86). The new second-generation colon capsule endoscopy is a safe and effective method for visualizing the colon and detecting colonic lesions. Sensitivity and specificity for detecting colorectal polyps appear to be very good, suggesting a potential for improved accuracy compared with the first-generation system. Further prospective and comparative studies are needed.