The question is addressed whether particular tumor necrosis factor-alpha (TNF-alpha) polymorphisms are associated with clinical course and outcome of human immunodeficiency virus type 1 (HIV-1) infection. The distribution of four TNF-alpha guanine (G) to adenosine (A) transition polymorphisms at positions -376, -308, -238, and -163 of the 5' promoter region of the TNF-alpha gene was studied in a nested case-control study among HIV-1-seropositive participants of the Amsterdam Cohort. None of the polymorphisms was significantly associated with long-term asymptomatic survival after HIV-1 infection compared with progression to clinical AIDS. Moreover, specific AIDS-defining illnesses or biologic phenotype of the HIV-1 virus were not associated with TNF-alpha alleles. The results of this study do not point toward a role for known TNF-alpha G to A transition polymorphisms in the clinical course of HIV-1 infection.