Purpose: To develop evidence-based colorectal cancer (CRC) screening guidelines for use in average-risk members of the Kaiser Permanente Medical Care Program in the United States. Methods: The guideline development team formulated the research questions for the literature review, with particular emphasis on the preferred choice of screening tests and the optimal interval to conduct screening. A systematic literature review was conducted examining the evidence underlying each problem formulation. Each recommendation was classified as “evidence based” or “consensus based” and the quality of underlying evidence was graded as A, B, C or I (for insufficient evidence). Results: We found grade “A” evidence supporting CRC screening in average-risk adults. There is insufficient evidence to determine which CRC screening modality is most effective in terms of the balance of benefits and potential harms. The evidence is strongest for fecal occult blood tests (FOBTs), supported by randomized clinical trials (Grade: "A"), and for flexible sigmoidoscopy (FS), supported by case-control and cohort studies (Grade: "B"). A consensus-based recommendation to combine FS and FOBT can be made based on grade C evidence. There is insufficient evidence to recommend for or against the use of colonoscopy or air contrast barium enema for CRC screening. The evidence base is strongest for performing FOBT at 2-year intervals, rather than 1 year, and for performing FS at 10-year intervals, rather than 5 years. Conclusions: Our evidence review and the guideline product are consistent with the U.S. Preventive Services Task Force. In distinction with other published guidelines, we found insufficient evidence to justify the use of colonoscopy for screening average-risk adults for CRC. We also found that currently recommended CRC screening intervals are more frequent than what is supported by the evidence. Full adoption of our guideline would be associated with fewer colonoscopy related complications, and reduced colonoscopy resource requirements. Less reliance on constrained colonoscopy resources will allow more patients to be screened for CRC, with minimal loss of screening effectiveness.