FOLFIRINOX has been commonly utilized to treat patients with pancreatic cancer; however, it can manifest with rare, significant adverse effects. In particular, 5-FU has been associated with cardiotoxic effects, including but not limited to ischemic events, myocarditis, cardiac arrhythmias, cardiac death, heart failure, as well as coronary vasospasm. Two common thought processes regarding the mechanism of cardiotoxicity with 5-FU include exacerbation of ischemia secondary to coronary vasospasm and direct cell injury to the myocardium. Management of cardiotoxic adverse effects includes discontinuing 5-FU therapy if the patient can tolerate an alternative regimen or initiating prophylactic antianginal treatments with very close monitoring of the patient while they receive 5-FU therapy. Here, we describe a case of a 77-year-old patient with stage III pancreatic cancer who developed coronary vasospasm after initiation of combination therapy including 5-FU. Additional studies to gain further understanding of 5-FU cardiotoxicity are warranted, especially considering the common use of this medication with regards to pancreatic cancer patients. Further research of this topic may benefit patient care, prevent cardiovascular events, and determine which patients may benefit from prophylactic therapy while receiving 5-FU.