Background Colon capsule endoscopy (CCE) represents a noninvasive technology that allows visualization of the colon without requiring sedation and air insufflation. A second-generation colon capsule endoscopy system (PillCam Colon 2) (CCE-2) was developed to increase sensitivity for colorectal polyp detection compared with the first-generation system. Objective To assess the feasibility, accuracy, and safety of CCE-2 in a head-to-head comparison with colonoscopy. Design and Setting Prospective, multicenter trial including 8 European sites. Patients This study involved 117 patients (mean age 60 years). Data from 109 patients were analyzed. Intervention CCE-2 was prospectively compared with conventional colonoscopy as the criterion standard for the detection of colorectal polyps that are ≥6 mm or masses in a cohort of patients at average or increased risk of colorectal neoplasia. Colonoscopy was independently performed within 10 hours after capsule ingestion or on the next day. Main Outcome Measurements CCE-2 sensitivity and specificity for detecting patients with polyps ≥6 mm and ≥10 mm were assessed. Capsule-positive but colonoscopy-negative cases were counted as false positive. Capsule excretion rate, level of bowel preparation, and rate of adverse events also were assessed. Results Per-patient CCE-2 sensitivity for polyps ≥6 mm and ≥10 mm was 84% and 88%, with specificities of 64% and 95%, respectively. All 3 invasive carcinomas were detected by CCE-2. The capsule excretion rate was 88% within 10 hours. Overall colon cleanliness for CCE-2 was adequate in 81% of patients. Limitations Not unblinding the CCE-2 results at colonoscopy; heterogenous patient population; nonconsecutive patients. Conclusion In this European, multicenter study, CCE-2 appeared to have a high sensitivity for the detection of clinically relevant polypoid lesions, and it might be considered an adequate tool for colorectal imaging.