The objective of this study was to investigate the spectrum and frequency of rare AIDS-defining diseases in the Swiss HIV Cohort Study. AIDS-defining diseases contributing less than 1% to the absolute number of all recorded AIDS-defining diseases in at least one of five periods (1988-1990, 1991-1992, 1993-1994, 1995-1996, 1997) were defined as being rare. A total of 9110 HIV-infected subjects were included in this study. Over the entire 9-year period, the following rare diseases were diagnosed: progressive multifocal leukoencephalopathy (n = 138), disseminated cryptococcosis (n = 67), visceral herpes simplex disease (n = 66), primary cerebral lymphoma (n = 65), indeterminate cerebral lesion (n = 50), cryptococcal meningitis (n = 34), Mycobacterium kansasii disease (n = 32), recurrent Salmonella septicemia (n = 22), intestinal isosporiasis (n = 21), candidiasis of the trachea, bronchi and lungs (n = 19), toxoplasma retinitis (n = 16), disseminated toxoplasmosis (n = 8), invasive cervical carcinoma (n = 8), extrapulmonary Pneumocystis disease (n = 5), disseminated histoplasmosis (n = 1) and disseminated coccidioidomycosis (n = 1). Rare diseases accounted for 7.3% of all AIDS-defining diseases over the entire 9-year period. Physicians should be aware of the likelihood of a broad spectrum of AIDS-defining diseases in HIV-infected patients.