BackgroundPolymorphisms of genes related to the immune response have been reported to confer susceptibility to Vogt-Koyanagi-Harada (VKH) disease. This study was carried out to determine whether zinc finger CCCH-type containing antiviral 1 (ZC3HAV1) and tripartite motif-containing protein 25 (TRIM25) genetic polymorphisms are associated with this disease.MethodsA total of 766 VKH patients and 909 healthy individuals were enrolled in this two-stage case-control study. Thirty-one tag single nucleotide polymorphisms (SNPs) of ZC3HAV1 and TRIM25 were genotyped by MassARRAY System and iPLEX Gold Genotyping Assay. Allele and genotype frequencies were analyzed by the χ2test or Fisher’s exact test. Cochran-Mantel-Haenszel test was used to assess the pooled odds ratio (OR) in the combined study. A stratified analysis was performed in terms of the major clinical features of VKH disease.ResultsWe found a statistically significant increased frequency of the minor A allele of ZC3HAV1 rs7779972 (P= 1.50 × 10− 4, pooled OR = 1.332, 95%CI = 1.149–1.545) in VKH disease as compared with controls by using the Cochran-Mantel-Haenszel test. The GG genotype of rs7779972 showed a protective association with VKH disease (P= 1.88 × 10− 3, OR = 0.733, 95%CI = 0.602–0.892). There was no difference regarding the frequency of the remaining SNPs between VKH cases and controls (allP> 2.08 × 10− 3). The stratified analysis showed no significant association of rs7779972 with the major clinical characteristics of VKH disease.ConclusionOur study indicated that the ZC3HAV1 variant rs7779972 might confer susceptibility to VKH disease in Han Chinese.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12920-023-01546-3.