Background: Crimean-Congo hemorrhagic fever (CCHF) is an acute viral hemorrhagic fever caused by the Crimean-Congo hemorrhagic fever virus (CCHFV). Nuclear factor (NF)-kappa B regulates the expression of hundreds of genes, including inflammatory and immunoregulatory, cell cycle regulating, and anti-apoptotic genes. NF-kappa BIA (I kappa B alpha) encodes an inhibitory version of the NF-kappa B proteins. Methods: This study is the first to investigate the association between NF-kappa B1-94W/D and NF-kappa BIA 3 -> UTR A -> G polymorphisms and CCHF using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Results: There was a significant difference in NF-kappa B1 - 94W/D genotype distribution between CCHF patients and control populations (p = 0.001). Comparison of the WW genotype with both WD and DD genotypes revealed that the difference between CCHF patients and controls was statistically significant (p = 0.043 for WD genotype, p = 0.018 for DD genotype). However, a significant deviation was found between patients with fatal CCHF and control populations (p = 0.025). The results show that patients with fatal CCHF with the DD genotype have a 4.06-times higher risk for CCHF compared to patients in the control group (odds ratio (OR) 4.06, 95% confidence interval (CI) 1.11-14.87). A significant difference in NF-kappa BIA 3 -> UTR A -> G polymorphisms was observed between CCHF patients and controls in both AA vs AG and AA vs GG (OR 2.04, p = 0.019; OR 2.01, p = 0.049, respectively). Conclusions: Our findings suggest that NF-kappa B1 - 94W/D and NF-kappa BIA 3 -> UTR A -> G polymorphisms may be valuable predictors of the clinical course in CCHF disease.