The aim of this study was to determine the outcome of patients with HIV-associated esophageal disease refractory to empiric antifungal therapy, both before and after the introduction of protease inhibitors. We reviewed the medical records of 629 consecutive HIV-infected patients with odynophagia, dysphagia, or both esophageal symptoms refractory to at least one week of empiric antifungal therapy who underwent endoscopy between January 1992 and January 1997 at Bellevue Hospital Center. Endoscopy identified an etiology in 96.2% of patients, with cytomegalovirus ulcers (40.0%) and idiopathic ulcers of the esophagus (26.6%) being the most common lesions found. Overall, 91.4% of patients had a response to disease-specific therapy. In patients taking protease inhibitors, recurrent symptoms were less common (26.5% vs 36.7%, P = 0.03) and median survival was longer (172 vs 125 weeks, P = 0.006) than in those who were not treated with these potent antiretroviral medications. Protease inhibitors have had a positive impact on the outcome of HIV-associated esophageal disease.