A total of 347 HIV-seropositive individuals attending the Department of Infections Diseases at Rigshospitalet in Copenhagen and 110 age- and sex- matched healthy controls not at risk for HIV infection were included in this study. Interferon γ (IFN-γ) production was measured in whole blood of 223 HIV-seropositive individuals (68 had developed AIDS at enrolment) and 99 healthy sex- and age-matched controls 4.5 hr after challenge with phytohemagglutinin. HIV-infected individuals for whom IFN-γ production was measured were followed with a median follow-up time of 2.89 years (range, 0.02-4.54 years) from the date of enrollment. Survival analysis was performed considering three different end points: (1) a CD4 count below 100 cells/mm³, (2) an AIDS diagnosis defined according to the 1993 Centers for Disease Control definition, and (3) death. The production of IFN-γ was highly increased in the blood of HIV-infected individuals without AIDS, but decreased in the blood of AIDS patients (both compared to controls). In the HIV-infected individuals, the total production of IFN-γ was positively correlated with the number of CD8⁺ T lymphocytes and with the number of CD16⁺/CD56⁺ natural killer cells and negatively correlated with serum levels of β₂-microglobulin. Low levels of IFN-γ, production were associated with an increased risk of experiencing a CD4 count below 100 cells/m³ and death, analyzed in both univariate analysis and in multivariate analysis adjusting for CD4 counts and age. Thus, changes in production of IFN-γ seem to be truly related to the risk for disease progression in HIV infection.