Background: Colorectal cancer (CRC) is the third most common cancer and the third leading cause of cancer deaths in the United States. The results of the randomized Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial conducted in the U.S. and the U.K. Once-Only randomized trial of flexible sigmoidoscopy (FSG) indicated that FSG screening is effective in reducing CRC incidence and mortality. However, it is not clear what fraction of the observed mortality reduction was actually due to early detection of CRC, as opposed to detection and removal of CRC precursors (adenomas). A mortality effect due to early detection per se should be revealed by a survival advantage for CRC cases in the screened versus control arm of PLCO. Methods: PLCO randomized 154,900 men and women to either an intervention (n = 77,445) or usual care (n = 77,455) arm. Eligible participants were 55 to 74 years of age at enrollment and had no history of trial cancers and no current treatment for cancer. Intervention arm individuals received screening for all gender-relevant PLCO cancers, including FSG for CRC at baseline and at 3 or 5 years. The median duration of the follow-up was 11.9 years with a maximum of duration of 13 years in each arm. CRC incidence and all-cause mortality data were obtained from participants’ medical records released to PLCO. CRC-specific survival was analyzed using Kaplan-Meier curves and proportional hazards modeling. Results: Kaplan-Meier curves demonstrated no significant difference in CRC-specific survival rates between arms (log-rank test, p = 0.12). In the intervention arm (n = 1008 cases), the 5 and 10 year CRC-specific survival rates were 76.1% and 70.1%, respectively, compared to corresponding usual care arm (n = 1291 cases) rates of 72.0% (5-year) and 66.6% (10-year). Within the intervention arm, interval cases (those diagnosed within 5 years after a negative screen) and those never receiving screening in PLCO had worse survival (HRs = 3.41 and 3.31, respectively) when compared to screen-detected cases. Conclusions: CRC-specific survival in PLCO was comparable across arms. This raises questions about the mortality benefit of early detection per se of CRC. Clinical trial information: NCT00002540