© 2018 American Society of Clinical Oncology. All rights reserved. Purpose We sought to determine the long-term risk of cardiovascular disease (CVD)-stroke and myocardial infarction-and congestive heart failure (CHF) in older patients with colorectal cancer, as well as to understand the roles that preexisting comorbidities and cancer therapy play in increasing this risk. Patients and Methods We evaluated individuals from the SEER-Medicare database with incident stage I to III colorectal cancer at age older than 65 years between January 1, 2000, and December 31, 2011 (n = 72,408) and compared these patients with a matched cohort of Medicare patients without cancer (n = 72,408). Results Median age at diagnosis of colorectal cancer was 78 years (range, 66 years to 106 years), and median follow-up was 8 years since diagnosis. The 10-year cumulative incidence of new-onset CVD and CHF were 57.4% and 54.5% compared with 22% and 18% for control, respectively (P , .001). The interaction between hypertension and chemotherapy was significant (P , .001) for CVD, and that between diabetes and chemotherapy was significant (P, .001) for CHF. Within the first 2 years since diagnosis, exposure to capecitabine alone increased CHF hazard (hazard ratio [HR], 3.6; 95% CI, 12.76 to 4.38) compared with exposure to fluorouracil alone. Conversely, patients who were treated with fluorouracil alone had a higher CVD hazard at , 2 years and . 2 years since diagnosis compared with patients who received capecitabine alone (, 2 years HR, 0.63; 95% CI, 0.53 to 0.75; . 2 years HR, 0.72; 95% CI, 0.62 to 0.84). Conclusion Older patients with colorectal cancer are at increased risk of developing CVD and CHF. Diabetes and hypertension interact with chemotherapy to increase the risk of cardiovascular morbidity. Future studies should assess the potential for personalized therapeutic options for those with preexisting morbidities and for structured monitoring for patients with a history of exposure to chemotherapy regimens, as well as explore the management of preexisting comorbidities to address long-term cardiovascular morbidity.