Susceptibility to silicosis is in part genetically determined. Polymorphisms in the promoter region of tumor necrosis factor (TNF)-alpha, a cytokine with a central role in the pathophysiology of silicosis, have been associated with predisposition to several infectious and inflammatory diseases. Polymorphisms at positions -308, -238, and -376 in the TNF-alpha promoter region were compared in nine patients with severe silicosis with International Labour Office (ILO) grade 3 nodularity, 112 patients with less severe silicosis (ILO grades 1/1 to 2/2), and 120 black South African gold miners without silicosis (ILO grades 0/0) in an age-frequency-matched case- control study. There were no significant differences between miners with less severe silicosis and controls at any loci in the TNF-alpha promoter region, but miners with severe silicosis were significantly more likely than controls to have -238A (33% versus 6%, Fisher's exact p value = 0.022) and -376A (33% versus 5%, Fisher's exact p value = 0.016). These alleles were in linkage disequilibrium (p < 0.001), and so were not independent. The association remained significant (Fisher's exact p values = 0.011 and 0.011, respectively) when analysis was limited to the majority tribe (Basotho), which included all subjects with severe silicosis. Subjects with severe silicosis were also significantly more likely to have the -308A allele (Fisher's exact p value = 0.034), but this result was confounded by ethnicity and was not significant within Basotho tribe members (Fisher's exact p value = 0.15). TNF-alpha promoter polymorphisms are associated with severe, but not less severe, silicosis in this population. A predominant effect on disease severity, rather than on disease frequency, appears to be a general feature of promoter polymorphism in diseases in which TNF-alpha has a critical role.