--- - |2+ Abstract Objective More people are living with the consequences of cancer and comorbidity. We describe frequencies of comorbidities in a colorectal cancer cohort and associations with health and well‐being outcomes up to 5 years following surgery. Methods Prospective cohort study of 872 colorectal cancer patients recruited 2010 to 2012 from 29 UK centres, awaiting curative intent surgery. Questionnaires administered at baseline (pre‐surgery), 3, 9, 15, 24 months, and annually up to 5 years. Comorbidities (and whether they limit activities) were self‐reported by participants from 3 months. The EORTC QLQ‐C30 and QLQ‐CR29 assessed global health/quality of life (QoL), symptoms, and functioning. Longitudinal analyses investigated associations between comorbidities and health and well‐being outcomes. Results At baseline, the mean age of participants was 68 years, with 60% male and 65% colon cancer. Thirty‐two per cent had 1 and 40% had ≥2 comorbidities. The most common comorbidities were high blood pressure (43%), arthritis/rheumatism (32%), and anxiety/depression (18%). Of those with comorbidities, 37% reported at least 1 that limited their daily activities. Reporting any limiting comorbidities was associated with poorer global health/QoL, worse symptoms, and poorer functioning on all domains over 5‐year follow‐up. Controlling for the most common individual comorbidities, depression/anxiety had the greatest deleterious effect on outcomes. Conclusions Clinical assessment should prioritise patient‐reported comorbidities and whether these comorbidities limit daily activities, as important determinants of recovery of QoL, symptoms, and functioning following colorectal cancer. Targeted interventions and support services, including multiprofessional management and tailored assessment and follow‐up, may aid recovery of health and well‐being in these individuals. - Psycho-Oncology, Volume 27, Issue 10, Page 2427-2435, October 2018.