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Objectives To systematically evaluate associations between comorbidities and differences in treatment decisions, outcomes, health-related quality of life (HRQoL), healthcare resource utilisation and costs, in patients with colon or rectal cancer.Design Systematic review.Data sources PubMed (Medline) and Embase databases were searched for studies published from January 2000 until January 2024.Eligibility criteria for selecting studies We included articles that compared the presence and absence of comorbidities, evaluated multiple comorbid conditions or used the Charlson Comorbidity Index, or variations such as the Charlson-Deyo Index. Primary and secondary outcome measures included cancer treatments, outcomes (including complications from treatments, survival and mortality rates), HRQoL, healthcare resource use and costs.Data extraction and synthesis Two independent reviewers used standardised methods to search, screen and code included studies. Risk of bias was assessed using the Joanna Briggs Institute checklists to ensure the quality of data. Findings were summarised narratively.Results After duplicates were removed, 15 394 hits were screened and 31 studies were selected for inclusion in this systematic review. Comorbidities were associated with a lower likelihood of receiving treatment and lower survival rates and HRQoL, alongside a higher likelihood of complications following treatment, higher mortality rates and higher healthcare resource use. There were very limited studies that reported on HRQoL and resource use, and none reporting data directly relating to the impact of comorbidities on costs. These results were consistent across North America, Europe, Australia and New Zealand.Conclusions For patients with colon and rectal cancer, comorbidities are associated with a lower likelihood of receiving treatments and poorer health outcomes. With global populations ageing, there is likely to be an increase in patients with colon and rectal cancer with comorbidities. Therefore, further research is necessary, especially to inform decisions regarding patient management and treatment, and to understand the implications on healthcare resource allocation, costs and HRQoL.