Background and Objective: Diagnosis of colorectal cancer after negative findings on endoscopic evaluation raises concern about the effectiveness of endoscopic screening. We contrast screening-detected cancers with cancers not detected by screening among participants assigned to flexible sigmoidoscopy (FSG) in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial to determine the reasons for the lack of detection of prevalent lesions. Design: Cancers detected within 1 year of a screening FSG with abnormal findings were classified as screening detected. All other cancers were categorized, based on cancer stage and years until detection, as either not detectable or prevalent but not detected at the time of screening. Setting/Patients: A total of 77,447 subjects in the multicenter PLCO trial. Main Outcome Measurements: A total of 977 colorectal cancers were diagnosed with a mean follow-up of 11.5 years. Results: A total of 243 (24.9%) cancers were screening detected, 470 (48.1%) were not detectable at screening, and 264 (27.0%) were considered prevalent but not detected. Among prevalent nondetected lesions, 35.6% (n = 94) were attributed to problems in patient compliance (58 never screened, 34 delayed colonoscopy follow-up, and 2 inadequate bowel preparation), 43.9% (n = 116) were attributable to a limitation in the FSG procedure (97 beyond the reach of the sigmoidoscope and 19 inadequate depth of insertion on FSG), and 20.5% (n = 54) were caused by endoscopist limitation (33 missed on FSG, 21 missed at initial colonoscopy) (P <.0001). Had colonoscopy instead of FSG been used for screening, an additional 15.6% and as many as 19.0% of cancers may have been screening-detected. Limitations: These estimates are reasonable approximations, but biological variability precludes precise determinations. Conclusions: Prevalent nondetected cancers were more often attributable to problems with patient compliance or limitations in the FSG procedure than to missed lesions. Colonoscopy instead of FSG could have moderately increased the detection of cancer via screening.