What is the effectiveness of colonoscopy in reducing colorectal cancer (CRC) mortality? Because we do not have direct evidence from a randomized, controlled trial (RCT), we must rely on indirect evidence. In this issue, Baxter and colleagues' case–control study (1) raises interesting and troubling questions about how much screening colonoscopy reduces CRC mortality. The authors used a province-wide administrative database in Ontario, Canada, to identify case patients who received a diagnosis of CRC from 1996 to 2001 and died by 2003. Five randomly selected controls who did not die of CRC were matched to each case patient. Exposure to previous colonoscopy was assessed from billing claims for case patients and controls. Among 10 292 case patients, 7.0% had previous colonoscopy, whereas among 51 460 controls, 9.8% had a previous colonoscopy. The odds ratio for the association between complete colonoscopy and CRC mortality reduction was 0.33 for left-sided lesions, which suggests a large mortality reduction. However, the result was dramatically different for right-sided lesions: An odds ratio of 0.99 indicated a roughly 1% mortality reduction, which is essentially none at all.