The esophagus is one of the most common sites of gastrointestinal involvement in human immunodeficiency virus (HIV)-infected patients, with at least 30% of the patients having esophageal symptoms at some point during the course of HIV infection. Esophageal ulcers are commonly caused by infections such as cytomegalovirus (CMV) or may be idiopathic. The clinical presentation of the various causes of esophageal ulcers are similar; therefore, a thorough endoscopic and histological workup is imperative to make a diagnosis and, consequently, to provide appropriate therapy. The widespread use of more effective antiretroviral therapy appears to have led to a decline in gastrointestinal opportunistic disorders in patients with acquired immunodeficiency syndrome (AIDS), including those involving the esophagus. Unfortunately, there are several reports of resistance of HIV-1 to multiple antiretroviral agents, and thus it is possible we will observe an increase in various opportunistic disorders again. The aim of this article is to provide a practical approach to the clinical, endoscopic, and histopathologic evaluation of esophageal ulcers in patients with AIDS.