The Tat protein of human immunodeficiency virus (HIV) is essential for viral replication and has extracellular pathogenic activity. We sought to determine whether the anti-Tat antibody response was predictive of disease progression in 144 HIV type 2 (HIV-2)-infected subjects observed longitudinally between 1985 and 2003. Sixty-eight percent of the subjects tested positive for anti-Tat antibodies, with reactivity notably established early after seroconversion and stably maintained over the course of infection. The risk and rate of progression to advanced HIV-2 AIDS was significantly higher in anti-Tat-negative subjects than in anti-Tat-positive subjects, extending the importance of this prognostic marker for HIV-2 AIDS.