BACKGROUND: Colorectal cancer (CRC) is the third most common cancer worldwide with over 1 million new cases diagnosed each year. Advances in treatment and survival are likely to have increased lifetime costs of managing the disease. Cost-of-illness (COI) studies are key building blocks in economic evaluations of interventions and comparative effectiveness research. We systematically reviewed and critiqued the COI literature on CRC. METHODS: We searched several databases for CRC COI studies published in English, between January 2000 and February 2011. Information was abstracted on: setting, patient population, top-down/bottom-up costing, incident/prevalent approach, payer perspective, time horizon, costs included, cost source, and per-person costs. We developed a framework to compare study methodologies and assess homogeneity/heterogeneity. RESULTS: A total of 26 papers met the inclusion criteria. There was extensive methodological heterogeneity. Studies included case-control studies based on claims/reimbursement data (10), examinations of patient charts (5), and analysis of claims data (4). Epidemiological approaches varied (prevalent, 6; incident, 8; mixed, 10; unclear, 4). Time horizons ranged from 1 year postdiagnosis to lifetime. Seventeen studies used top-down costing. Twenty-five studies included healthcare-payer direct medical costs; 2 included indirect costs; 1 considered patient costs. There was broad agreement in how studies accounted for time, but few studies described costs in sufficient detail to allow replication. In general, costs were not comparable between studies. CONCLUSIONS: Methodological heterogeneity and lack of transparency made it almost impossible to compare CRC costs between studies or over time. For COI studies to be more useful and robust there is need for clear and rigorous guidelines around methodological and reporting "best practice."