Fibrosing alveolitis (FA) is characterized by persistent inflammation and elevated production of tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1beta), and interleukin-1 receptor antagonist (IL-1ra) in the lung. Single base variations at position +2018 in the IL-1ra gene (IL-1RN) and position -308 in the TNF-alpha gene (TNF-A) are overrepresented in other chronic inflammatory disease populations. We have tested the hypothesis that predisposition to FA may also be influenced by these polymorphisms by genotyping 88 cases and matched controls from England and 61 cases and 103 unmatched controls from Italy. The rarer allele for IL-1RN and TNF-A was designated allele 2 in each case. For IL-1RN allele 2, in the English group, the relative odds of FA were increased in homozygous subjects by an odds ratio (OR) of 10.2 (95% confidence intervals [CI], 1.26 to 81.4; p = 0.03) and for carriers by an OR of 1.85 (95% CI, 0.94 to 3.63; p = 0.075). In the Italian population, the risk of FA was increased, in IL-1RN allele 2 homozygotes (OR, 2.54; 95% CI, 0.68 to 9.50; p = 0.2) and in carriers (OR 2.40; 95% CI, 1.26 to 4.60; p = 0.008). Carriage of TNF-A allele 2 was also associated with increased risk of FA in the English (OR, 1.85; 95% CI, 0.94 to 3.63; p = 0.075) and Italian (OR, 2.50; 95% CI, 1.14 to 5.47; p = 0.022) populations. These data suggest IL-1RN (+2018) allele 2 and TNF-A (-308) allele 2 confer increased risk of developing FA and, therefore, that unopposed IL-1beta and/or excessive TNF-alpha may play a pathophysiologic role in this condition.