We examined association between HSPA1B (+1267A/G, rs1061581), TNF-α (–308G/A, rs1800629), and S100B (C/T, rs9722) genes polymorphisms and chronic mercury poisoning (CMP). PCR-RFLP analysis was used to examine a cohort consisting of 128 workers who were chronically exposed to mercury vapor; workers were distributed into two groups. The group 1 was made up of workers with long working experience who didn’t have CMP (n = 46), the group 2 included patients with long-term CMP period (n = 82). In addition, we estimated frequencies of rs1061581genotypes in 298 practically healthy men from regional sub-population (group 3). HSPA1B (+1267A/G) polymorphic variant was established to have more frequent carriage of both minor G allele (р = 0.003) and a rare GG homozygote (р = 0.005) in the group 2 against the group 1. 23.2 % patients from the group 2 turned out to have GG genotype and CMP was diagnosed in 95 % people who had it. We didn’t detect any differences in genotypes distribution among people from the examined occupational cohort (groups 1 and 2) against the group 3. GG-HSP1AB (+1267A/G) homozygous genotype was shown to be associated with CMP risks (OR = 13.57, p < 0.0001, recessive model). Haplotype G–G (rs1061581–rs1800629) carriers were established to run 2.6 higher risks of CMP occurrence (р = 0.0098), and there was a significant linkage disequilibrium D' = 0.459 (р = 0.0004) between a pair of the abovementioned polymorphic loci. These data indicate that there is genetic interaction between HSPA1B (+1267A/G) and TNF-α (–308G/A) loci in the examined cohort. Overall, these results indicate that carriers of GG-HSPA1B (+1267A/G) genotype run high predictive risks of CMP occurrence.