To assess the role of IL-12Bpro and GSTP1 polymorphisms on induced interleukin (IL)-12p40 production in respect to silicosis development, we examined their distribution in 63 silicosis patients and 165 healthy donors. Decreased frequencies of IL-12Bpro-2 allele (42% vs 62.5%, P = 0.0042) and genotype 22 (19% vs 40%, P = 0.02) in patients compared with exposed healthy donors suggested their protective role in silicosis susceptibility. The GSTP1 A/G polymorphism was also associated with silicosis susceptibility. The allele G and genotype GG were overrepresented among patients than among healthy men (36% vs 23%, P = 0.013; 14% vs 2%, P(c) = 0.012). Also, patients' peripheral blood mononuclear cell (PBMC) produced higher IL-12p40 than healthy donors' depending on both IL-12Bpro and GSTP1 polymorphisms. In conclusion, homozygosity of high producer IL-12p40 genotype IL-12Bpro-11 and GSTP1-GG had the highest genetic risk of silicosis development in Bulgarian miners.