Background: Fluoropyrimidines are mainstay chemotherapeutics in the treatment of gastrointestinal cancers and are also used to treat breast cancer and head and neck cancers. However, 5-flourouracil (5-FU) and capecitabine may induce cardiotoxicity that mostly presents as acute coronary syndromes. We compared the incidence of cardiotoxicity induced by 5-FU and capecitabine in patients with colorectal cancer and sought to identify risk markers for cardiotoxicity. Methods: We reviewed all consecutive patients with colorectal cancer who received 5-FU or capecitabine at one institution in the neoadjuvant (2007–2016), adjuvant (2000–2016) or metastatic setting (2007–2016). Results: Totally, 995 patients received 5-FU and 1241 received capecitabine. The incidence of cardiotoxicity induced by 5-FU was 5.2% [95% confidence interval (CI): 3.8–6.6%] and 4.1% (95% CI: 3.0–5.2%) induced by capecitabine (p =.21). The most common events were angina without ischemia (5-FU: 1.6%, capecitabine: 1.3%, p =.53), angina with ischemia on ECG (5-FU: 0.9%, capecitabine: 0.8%, p =.53), unspecified chest pain (5-FU: 0.9%, capecitabine: 0.6%, p =.34), ST-elevation myocardial infarction (5-FU: 0.5%; capecitabine: 0.4%, p =.76) and non-ST-elevation myocardial infarction (5-FU: 0.7%, capecitabine: 0.5%, p =.50). Cardiac arrest or sudden death occurred in 0.5 and 0.4%, respectively (p = 1). No risk markers for cardiotoxicity induced by 5-FU were identified. In the capecitabine group, ischemic heart disease was a risk marker (odds ratio: 2.9, 95% CI: 1.2–7.0, p =.016). Conclusions: Five percent of patients treated with 5-FU developed cardiotoxicity and 4% treated with capecitabine. Ischemic heart disease was a risk marker for cardiotoxicity induced by capecitabine.