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Dengue virus infection (DEN) is one of the most prevalent arbovirus diseases in the tropical and subtropical areas. Some human leukocyte antigen (HLA) alleles have been reported to be a protective or risk factor to DEN. Due to the limited sample sizes and regional limitations, the results of individual studies were various. This meta-analysis aimed at investigating the relationship between HLA alleles and dengue disease. Relevant studies of the relationship between HLA and dengue disease were searched through PubMed, Embase, Web of science, and Cochrane databases. Subgroups according to ethnicity or sub-alleles and sensitivity analysis were used to explore the potential source of heterogeneity, which was performed to confirm the findings. The relationships between HLA and dengue disease were defined by odds ratios (ORs) with a 95% confidence interval (CI). Fourteen studies were finally confirmed. Results indicated that A*0203 (OR = 2.19, 95% CI = 1.30–3.69) and A*24 in the Asian group (OR = 1.44, 95% CI = 1.21–1.71) were positively associated with an increased risk of DEN when compared with normal controls. A*33 (OR = 0.49, 95% CI = 0.34–0.69) in Southeast Asia was negatively associated with DEN when compared with normal controls, suggesting a protective role against DEN. In addition, DRB1*11 (OR = 4.10, 95% CI = 1.23–13.69) was positively associated with severe dengue (SD) when compared with dengue fever, whereas DRB1*03 (OR = 0.48, 95% CI = 0.28–0.82) and DRB1*09 (OR = 0.73, 95% CI = 0.55–0.96) were negatively associated with SD when compared with normal controls. The meta-analysis confirmed that HLA-A*0203, A*24, A*33, DRB1*03, DRB1*09, and DRB1*11 have significantly affected dengue disease, and the associations are related to race and regions. [ABSTRACT FROM AUTHOR]