Major aphthous ulcers are associated with a high degree of morbidity in patients infected with human immunodeficiency virus. A large representative cohort infected with human immunodeficiency virus was examined to evaluate the prevalence of major aphthous ulcers, demographic data of patients with major aphthous ulcers, and the usage of major aphthous ulcers as a marker for immune deterioration. The effects of tobacco smoking and the use of specific antibiotics, trimethoprim/sulfamethoxazole or dapsone, on the development of major aphthous ulcers was also investigated. In a population of 767 persons infected with human immunodeficiency virus, major aphthous ulcers were found at a prevalence rate of 3.1% (24 patients). This type of lesion did not show any predilection for human immunodeficiency virus transmission category, ethnic group, or gender. Persons who received trimethoprim/sulfamethoxazole or dapsone or had a history of tobacco smoking showed a decreased prevalence of major aphthous ulcers. All patients (100%) with major aphthous ulcers had CD4+ cell counts below 100 cells/mm3, but only 50% had a previous acquired immunodeficiency syndrome defining illness. Major aphthous ulcers in persons infected with human immunodeficiency virus are suggestive of severe immune suppression and may serve as a marker for human immunodeficiency virus disease progression.