The esophagus is frequently exposed to radiation during treatment of advanced stages of common cancers such as lung, breast, and esophagus. However, symptomatic radiation esophagitis requiring endoscopic and histologic evaluation occurs quite rarely, affecting less than 1% of patients receiving radiation treatment. Symptoms occur acutely, generally within the first 2 months. Patients typically present with nonspecific symptoms such as dysphagia and odynophagia. Endoscopic changes such as erythema and ulceration are also nonspecific and nondiagnostic. Biopsies from affected areas show variable inflammatory changes and radiation-related atypia of endothelial and stromal cells. Such atypia mimics cytomegalovirus cytopathic changes, which are ruled out through absence of immunostaining. Radiation esophagitis is thus clinically unsuspected and endoscopically and histologically quite different from the more common and familiar radiation proctitis for which angioectasia is the predominant finding.