Background Observational studies indicate that physical activity (pa) is strongly associated with improved disease outcomes in colon cancer survivors, but a randomized controlled trial is needed to determine whether the association is causal and whether new policies to promote exercise are justified. Purpose The co.21 Colon Health and Life-Long Exercise Change (challenge) trial undertaken by the National Cancer Institute of Canada Clinical Trials Group (ncic ctg) is designed to determine the effects of a structured pa intervention on outcomes for survivors of high-risk stage ii or iii colon cancer who have completed adjuvant therapy within the previous 2–6 months. Methods Trial participants (n = 962) will be stratified by centre, disease stage, body mass index, and performance status, and will be randomly assigned to a structured pa intervention or to general health education materials. The pa intervention will consist of a behavioural support program and supervised pa sessions delivered over a 3-year period, beginning with regular face-to-face sessions and tapering to less frequent face-to-face or telephone sessions. The primary endpoint is disease-free survival. Important secondary endpoints include multiple patient-reported outcomes, objective physical functioning, biologic correlative markers, and an economic analysis. Summary Cancer survivors and cancer care professionals are interested in the potential role of PA to improve multiple disease-related outcomes, but a randomized controlled trial is needed to provide compelling evidence to justify changes in health care policies and practice.