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Background/objective: Dengue, an emerging and re-emerging viral disease, is a major public health problem. The aim of this study was to investigate the influence of KIRs genes polymorphism and KIRs genotypes in susceptibility of dengue virus infection and disease severity in a population from Burkina Faso through a case-control study.Methods: KIRs genes determination were performed using PCR-SSP in 50 patients infected by dengue virus (DENV) and 54 Healthy controls (HC) subjects which never having infected by DENV.Results: Data analysis showed significant association between frequencies of three KIR genes and dengue virus infection (DF): KIR2DL2 (OR: 7.32; IC: 2.87-18.65; P < 0.001); KIR2DL5A (OR: 15.00, IC: 5.68-39.59; P < 0.001) and KIR2DL5B (OR: 11.43; IC: 4.42-29; P < 0.001). While, KIR3DL3 (OR: 0.13, IC: 0.052-0.32; P < 0.001) and KIR2DS5 (OR: 0.12; IC: 0.04-0.30; P < 0.001) were associated with protection against DF. KIR2DL4 (OR: 9.75; IC95%: 1.33-70.97; p: 0.03) and KIRD3DL1 (OR: 12.00; IC95%: 1.60-90.13; p: 0.02) were associated with an increased risk in the development of secondary dengue infection (SDI).Conclusion: The results suggest a contribution of KIR2DL2, KIR2DL5A and KIR2DL5B genes in the susceptibility of DF development. While, KIR3DL3 and KIR2DS5 were found to be associated with protection against DF development by enhancing both the innate and acquired immune responses.