The aim of the current study is to evaluate the possible correlation between the single-nucleotide polymorphisms (SNP) of HOX transcript antisense intergenic RNA (HOTAIR) and the clinical characteristics of diabetic retinopathy (DR). Four loci of HOTAIR SNPs, including rs920778 (T/C), rs12427129 (C/T), rs4759314 (A/G), and rs1899663 (G/T), were genotyped via the TaqMan allelic discrimination for 276 DR individuals and 452 non-DR patients. The distribution frequency of HOTAIR SNP rs12427129 CT [adjusted odds ratio (AOR): 1.571, 95% CI: 1.025–2.408, p = 0.038], HOTAIR SNP rs12427129 CT+TT (AOR: 1.611, 95% CI: 1.061–2.446, p = 0.025), and HOTAIR SNP rs1899663 TT (AOR: 2.443, 95% CI: 1.066–5.595, p = 0.035) were significantly higher in the DR group. Moreover, the proliferative diabetic retinopathy (PDR) subgroup revealed a significantly higher distribution of HOTAIR SNP rs12427129 CT+TT (AOR: 2.016, 95% CI: 1.096–3.710, p = 0.024) and HOTAIR SNP rs1899663 TT (AOR: 4.693, 95% CI: 1.765–12.479, p = 0.002), and the distribution frequencies of HOTAIR SNP rs12427129 CT (AOR: 3.722, 95% CI: 1.555–8.909, p = 0.003), HOTAIR SNP rs12427129 CT+TT (AOR: 4.070, 95% CI: 1.725–9.600, p = 0.001), and HOTAIR SNP rs1899663 TT (AOR: 11.131, 95% CI: 1.521–81.490, p = 0.018) were significantly higher in the female PDR subgroup. Regarding the clinical characters, the DR patients with HOTAIR SNP rs1899663 GT+TT revealed a significantly shorter duration of diabetes compared to the DR patients with HOTAIR SNP rs1899663 GG (10.54 ± 8.19 versus 12.79 ± 7.73, p = 0.024). In conclusion, HOTAIR SNP rs12427129 and rs1899663 are strongly correlated to the presence of DR, especially for a female with PDR.