Tumor necrosis factor-␣ (TNF) is recognized as a central mediator of mineral dust-induced lung fibrosis, and genetic polymorphisms of the TNF promoter have been reported to influence levels of TNF production. To assess whether polymorphisms within the TNF promoter gene are associated with susceptibility to coal workers' pneumoconiosis (CWP), the DNA of 78 coal miners was typed for G-to-A transitions at positions Ϫ238 and Ϫ308. Our results show that frequency of A Ϫ308 genotype (T2) is significantly overpresented in coal miners with CWP (50%), as compared with miners without CWP (25%) and controls (29%). After correction for cumulative dust exposure and smoking, the A Ϫ308 transition genotype is still associated with the presence of CWP (OR ϭ 3.0, 95%CI ϭ 1.0-9.0). Both A Ϫ238 and A Ϫ308 transition genotypes were related to TNF release from endotoxin-stimulated blood monocytes; only the A Ϫ238 transition and not the A Ϫ308 transition was associated to coal dust-induced TNF release. In summary, this study shows that the A Ϫ308 transition is related to CWP, but this relation is not paralleled by a different TNF release in this genotype. A larger number of patients coupled to frequent TNF release are required to evaluate genotype screening to estimate individual health risks for effects of coal mine dust exposure.