The relationship between radiation and/or chemotherapy and the development of Barrett's and/or multilayered epithelium has not been investigated before. We ascertained a group of patients exposed to radiation and/or chemotherapy and an unexposed group to compare the prevalence rates of Barrett's epithelium and multilayered epithelium at the time of endoscopy in these two groups. Barrett's epithelium was found in ten of the 19 (53%) exposed patients, compared to eight of 38 (21%) unexposed subjects (P = 0.02). Six of 19 (32%) exposed patients had multilayered epithelium, compared to four of 38 (11%) unexposed subjects (P = 0.06). Twelve of the 19 exposed patients (63%) had either Barrett's or multilayered epithelium, in contrast to ten of 38 (26%) unexposed subjects (P = 0.01). Those with exposure to both chemotherapy and radiation had a significant increase in the risk for Barrett's and/or multilayered epithelium (P = 0.003). This study suggests a relationship between exposure to a combination of radiation and chemotherapy and the development of Barrett's and/or multilayered epithelium.