Objective: The aim of this study was to investigate the role of multidrug transporter P-glycoprotein 1 (MDR1), cytochrome P450 isozyme 2D6 (CYP2D6) and C-C chemokine receptor 5 (CCR5) genes in the mortality of patients with Crimean-Congo Hemorrhagic Fever (CCHF). Material and Methods: Fifteen patients under drug therapy and conventional supportive measures were investigated. Diagnosis of the patients was confirmed by ELISA and/or reverse transcription-polymerase chain reaction (RT-PCR) technique. Clinical and laboratory features of three cases with fatal outcomes were compared with those of twelve patients with non-fatal CCHF. Genomic DNA was isolated from pheripheral blood samples and PCR based reverse hybridization strip assay was used for the genotyping. Results: The mortality rate was 20% (3/15) in this study. In two fatal cases the MDR1 gene had homozygous point mutation and in one fatal case heterozygous point mutation. All the fatal cases had poor drug metabolizer genotypes of CYP2D6 gene. Of the twelve surviving patients, three had heterozygous mutation in the MDR gene while only one had homozygous mutation of the same gene. Drug metabolizer genotypes of CYP450 gene were normal in all surviving patients. In fatal cases, ratios of mutable MDR1 and poor drug metabolizer genotypes of CYP450 genes were higher than those in non-fatal cases. The CCR5 gene was normal in all cases. Conclusion: Hypoexpression of CYP2D6 alleles and mutation in MDR I gene could cause impaired drug metabolism and/or lead to therapeutic failure in the CCHF patients. MDR1 and CYP2D6 genes may play a crucial role in pharmacokinetics, immunological response and drug metabolism in the management of CCHF infection. Further studies are necessary to substantiate these findings.