Background Colon capsule endoscopy (CCE) is a technology that might contribute to colorectal cancer (CRC) screening programs as a filter test between fecal immunochemical testing and standard colonoscopy. The aim was to systematically review the literature for studies investigating the diagnostic yield of second-generation CCE compared with standard colonoscopy. Methods A systematic literature search was performed in PubMed, Embase, and Web of Science. Study characteristics including quality of bowel preparation and completeness of CCE transits were extracted. Per-patient sensitivity and specificity were extracted for polyps (any size,≥10mm,≥6mm) and lesion characteristics. Meta-analyses of diagnostic yield were performed. Results The literature search revealed 1077 unique papers and 12 studies were included. Studies involved a total of 2199 patients, of whom 1898 were included in analyses. The rate of patients with adequate bowel preparation varied from 40% to 100%. The rates of complete CCE transit varied from 57% to 100%. Our meta-analyses demonstrated that mean (95% confidence interval) sensitivity, specificity, and diagnostic odds ratio were: 0.85 (0.73-0.92), 0.85 (0.70-0.93), and 30.5 (16.2-57.2), respectively, for polyps of any size; 0.87 (0.82-0.90), 0.95 (0.92-0.97), and 136.0 (70.6-262.1), respectively, for polyps ≥10 mm; and 0.87 (0.83-0.90), 0.88 (0.75-0.95), and 51.1 (19.8-131.8), respectively, for polyps ≥6mm. No serious adverse events were reported for CCE. Conclusion CCE had high sensitivity and specificity for per-patient polyps compared with standard colonoscopy However, the relatively high rate of incomplete investigations limits the application of CCE in a CRC screening setting.