Background: Colorectal cancer (CRC) remains the 4^th most common cancer in the United States. Thus the identification of effective and safe prevention methods remains important. While long-term use of COX-2 inhibitors, NSAIDs, and aspirin are associated with a reduced risk of CRC, the cardiovascular (CV) toxicity of COX-2 inhibitors and NSAIDs inhibits use in the prevention setting. Aspirin (ASA) does not confer risk of CV side effects and is a promising chemopreventive agent for CRC, but risks include gastrointestinal side effects and bleeding. Preclinical data suggest that intermittent dosing of aspirin would retain efficacy, with reduced toxicity [Mohammed, AACR 2018, NCI-N01-CN-250026]. Methods: This ongoing double-blind placebo-controlled randomized trial will enroll 90 subjects (men and women) to three arms: daily oral ASA 325 mg for 12 weeks (N = 40); intermittent aspirin 325 mg daily (4 cycles, alternating 3 weeks aspirin/placebo for a total of 12 weeks, N = 40); or daily placebo for 12 weeks (N = 10). The primary objective is to test for the equivalence of the two aspirin schedules, as demonstrated by similar changes in the ratio of cell proliferation to apoptosis in rectal biopsy samples (Ki67: Bax). Secondary endpoints include spectral markers of colon cancer risk and DNA methylation changes. Eligibility requirements include a history of colorectal adenoma (any grade), and no history of the following: invasive malignancy in the past 2 years; chronic renal or liver disease; unstable angina, hemorrhagic stroke or uncontrolled hypertension; anemia, peptic ulcer, gastrointestinal bleeding, active colitis, or inflammatory bowel disease. Participants must not have taken aspirin, other NSAIDs, or COX-2 inhibitors 3 weeks prior to the intervention; alcohol use < 2 drinks/day. They will undergo blood draws and rectal biopsies at entry, at 9 weeks, and at end of intervention. A 3-month follow-up visit is planned. Statistical analyses will be based on 32 evaluable subjects in each of the two aspirin arms (allowing for drop-outs); we will have 81% power to detect a change in the Ki67:Bax ratio of -3.0 to +3.0, based on the standard deviation of similar data from an ongoing trial. Enrollment began in January 2018. Funding: NCI #HHSN2612201200035I. Clinical trial information: NCT02965703