To evaluate the effectiveness of colorectal cancer (CRC) screening in asymptomatic adults. A search was conducted of the Medline, Embase, and the Cochrane Library databases. A targeted search of PubMed was conducted for on-topic randomized controlled trials (RCTs). Meta-analysis across 4 RCTs for guaiac fecal occult blood testing (gFOBT) and flexible sigmoidoscopy (FS) screening showed a reduction of 18% (risk ratio [RR], 0.82; 95% CI [CI], 0.73-0.92) and 26% (RR, 0.74; 95% CI, 0.67-0.83) in CRC mortality for the screening group compared to controls, respectively. The number needed to screen (NNS) were 377 (95% CI, 249-887) and 864 (95% CI, 672-1266) for gFOBT and FS screening, respectively. A reduction of 8% and 27% in incidence of late-stage CRC was also observed for gFOBT and FS screening, respectively, but both had no significant effect on all-cause mortality. A single RCT found that screening with immunochemical fecal occult blood test (iFOBT) had no significant impact on CRC mortality (RR, 0.88; 95% CI, 0.72-1.07). Screening with FS has potential harms such as perforation, major and minor bleeding, and death from the procedure or from follow-up colonoscopy. gFOBT and FS screening reduce CRC mortality and incidence of late-stage disease. The absolute effect and NNS were much more favorable for older adults (= 60 years), suggesting that a targeted screening approach may avoid exposing younger adults to the harms of CRC screening, from which they are unlikely to derive any significant benefit. Although there is insufficient RCT evidence on the impact of iFOBT on mortality outcomes. compared to gFOBT, this test showed higher sensitivity and comparable specificity, indicating the need to update and reevaluate the evidence in light of future high-quality research. The protocol for this systematic review have been published with PROSPERO 2014: CRD42014009777.