Background: Previous estimates of the adenoma miss rate with optical colonosco py (OC) are hindered by the use of OC as its own reference standard. Objective: To evaluate the frequency and characteristics of colorectal neoplasms that are m issed prospectively on OC by using virtual colonoscopy (VC) as a separate refere nce standard. Design: Prospective, multicenter screening trial. Setting: 3 medic al centers. Participants: 1233 asymptomatic adults who underwent same day VC an d OC. Measurements: Colorectal neoplasms (adenomatous polyps) missed at OC befor e VC results were unblinded. Results: Fourteen (93.3%) of 15 nonrectal neoplasm s were located on a fold; 10 (71.4%) of these were located on the backside of a fold. Five (83.3%) of 6 rectal lesions were located within 10 cm of the anal v erge. Limitations: Estimation of the OC miss rate depended on polyp detection on both VC and second look OC and therefore under estimates the true OC miss rat e, particularly for smaller polyps. Conclusions: Most clinically significant ade nomas missed prospectively on OC are located behind a fold or near the anal verg e. The 12%OC miss rate for large adenomas (≥10 mm) when state of the art 3 dimensional VC is used as a separate reference standard is increased from the previous 0%to 6%estimates derived by using OC as its own reference standard. Background: Previous estimates of the adenoma miss rate with optical colonosco py (OC) are hindered by the use of OC as its own reference standard. Objective: To evaluate the frequency and characteristics of colorectal neoplasms that are m is prospectively on OC by using virtual References: 3 medic al centers. Participants: 1233 asymptomatic adults who underwent same day VC an d OC. Measurements: Colorectal neoplasms (adenomatous polyps) missed at Results: Fourteen (93.3%) of 15 nonrectal neoplasm s were located on a fold; 10 (71.4%) of these were located on the backside of a fold. Five (83.3%) of 6 rectal lesions were located within 10 cm of the anal v erge. Limitations: Estimation of the OC miss rate depended on polyp detection on both VC and second look OC and therefore under estimates the true OC miss rat e, particularly for smaller polyps. Con clustering: Most clinically significant ade nomas missed prospectively on OC are located behind a fold or near the anal verg e. The 12% OC miss rate for large adenomas (≥ 10 mm) when state of the art 3 dimensional VC is used as a separate reference standard is increased from the previous 0% to 6% estimates derived by using OC as its own reference standard.