Background Screening decreases colorectal cancer (CRC) morbidity and mortality, yet remains underutilized. Screening breakdowns arise from lack of uptake and failure to follow-up after a positive screening test. Objectives Systems of support to increase colorectal cancer screening and follow-up (SOS) is a randomized trial designed to increase: (1) CRC screening and (2) follow-up of positive screening tests. The Chronic Care Model and the Preventive Health Model inform study design. Methods The setting is a large nonprofit healthcare organization. In part-1 study, patients age 50-75 due for CRC screening are randomized to one of 4 study conditions. Arm 1 receives usual care. Arm 2 receives automated support (mailed information about screening choices and fecal occult blood tests (FOBT)). Arm 3 receives automated and assisted support (a medical assistant telephone call). Arm 4 receives automated, assisted, and care management support (a registered nurse provides behavioral activation and coordination of care). In part-2, study patients with a positive FOBT or adenomas on flexible sigmoidoscopy are randomized to receive either usual care or nurse care management. Primary outcomes are: 1) the proportion with CRC screening, 2) the proportion with a complete diagnostic evaluation after a positive screening test. Results We sent recruitment letters to 15,414 patients and 4675 were randomized. Randomly assigned treatment groups were similar in age, sex, race, education, self-reported health, and CRC screening history. Conclusions We will determine the effectiveness and cost effectiveness of stepped increases in systems of support to increase CRC screening and follow-up after a positive screening test over 2 years.