Acute esophagitis and esophageal strictures typically occur after local radiation therapy to the thoracic field. Toxicity is usually limited to the field of radiation and potentially augmented by concomitant use of chemotherapy, however esophageal stricturing due to chemotherapy alone is exceedingly rare. Gastrointestinal toxicity has been previously reported in the setting of 5-fluorouracil (5-FU)-based chemotherapy with abnormal thymidylate synthase or dihydropyrimidine dehydrogenase activities. We present a unique case of isolated chemotherapy-induced esophageal stricture in the setting of stage IIIa rectal adenocarcinoma which presented shortly after initiation of treatment with 5-FU-based chemotherapy in a patient with normal thymidylate synthase and dihydropyrimidine dehydrogenase assays. These findings prompt further investigation of pathways and potential risk factors leading to esophageal toxicity in patients treated with 5-FU-based chemotherapy.