BACKGROUND Dry eye disease (DED) is a chronic dysfunction of the ocular surface and has become an important public problem. Vitamin D receptor (VDR) gene polymorphism has been found to be associated with different kinds of diseases. The relationship between single nucleotide polymorphisms (SNPs) in the VDR gene should be studied. MATERIAL AND METHODS In the present case-control study, we investigated the association of VDR gene polymorphism with DED risk. Clinical data including age, gender, body mass index (BMI, kg/m²), smoking history, diabetes, and blood pressure were recorded. Serum 25-hydroxy vitamin D (25[OH]D) was chosen as the main parameter that reflected the level of vitamin D. We identified SNPs of VDR gene Apa-1, Bsm-1, Fok-1, and Taq-1 in both DED cases and healthy controls. RESULTS A total of 124 DED cases and 135 healthy controls were included in this study. It was reported that aa in Apa-1 (OR=2.803, 95% CI, 1.350-5.820) and tt in Taq-1 (OR=0.362, 95% CI, 0.141-0.930) were associated with increased the risk of DED. Analysis of the allele frequencies of VDR gene polymorphisms among DED patients and healthy controls showed that allele differences in Apa-1 were significantly associated with higher risk. CONCLUSIONS SNPs of VDR gene (Apa-1 and Taq-1) were associated with the risk of DED. No significant association of Bsm-1 and Fok-1 in VDR gene demonstrated significant effect in the incidence of DED. Thus, we found that several SNPs of VDR gene could provide significant pathogenic effects in the risk of DED.