Objectives: Capsule colonoscopy is an additional screening modality for colorectal cancer. Secondgeneration capsule colonoscopy (CC2) may have improved efficacy in the detection of colon adenomas as compared with prior devices. The purpose of this study was to evaluate the performance of CC2 in the detection of polyps in symptomatic and screening patients in the USA. Design: Prospective, multicentre study. Setting and participants: Two academic medical centres and two private practice facilities, evaluating patients with indications for colonoscopy. Methods: Patients underwent capsule colonoscopy procedure using magnesium citrate as a boost, followed by colonoscopy on the same day. The main outcome measurement was accuracy of CC2 for the detection of colorectal polyps ≥6 and ≥10 mm as compared with conventional colonoscopy. Results: 51 patients were enrolled, 50 of whom had CC2 and colonoscopy examinations and were included in the accuracy analysis. 30% and 14% of patients had polyps ≥6 and ≥10 mm, respectively. For lesions ≥10 mm identified on conventional colonoscopy, CC2 sensitivity was 100% (95% CI 56.1% to 100%) with a specificity of 93.0% (79.9% to 98.2%). For polyps ≥6 mm, the CC2 sensitivity was 93.3% (66.0% to 99.7%) and the specificity was 80.0% (62.5% to 90.9%). There was a 61% adequate cleansing rate with 64% of CC2 procedures being complete. Conclusions: In the initial US experience with CC2 there was adequate sensitivity for detecting patients with polyps ≥6 mm in size. Magnesium citrate was inadequate as a boost agent. Trial registration number: NCT01087528.