Recent studies have shown that the long non-coding RNA HOTAIR plays critical roles in tumor biology, including cancer progression and metastasis. However, the potential biological role HOTAIR in tumor escape remains undefined. Here, HOTAIR expression was measured in sixty paired gastric cancer (GC) tissue samples by real-time PCR, and then subjected to correlation analysis with human leukocyte antigen (HLA)-G levels which show close links with tumor escape mechanisms. Significant HOTAIR overexpression was observed in GC tissues, as well as strong positive correlations with HLA-G levels in both tissue and peripheral blood samples, detected by real-time PCR and ELISA assays respectively. Further gain- and loss-of-function studies indicated that HLA-G could be upregulated HOTAIR at both mRNA and secretion levels in vitro. On the other hand, bioinformatics analysis indicated the interaction between HOTAIR and miR-152, which shows potential regulation on HLA-G. And, altered miR-152 expression in GC tissues was also identified, and showed negative correlation with HOTAIR expression. Moreover, the negative regulation of miR-152 on HLA-G was verified in GC cells, while miR-152 induced decrease of HLA-G 3'UTR activity could be attenuated by HOTAIR co-overexpression with the assistant of mutation studies. Therefore, it was concluded that HOTAIR overexpression might also get involved in tumor escape mechanisms, involving HLA-G upregulation via inhibiting miR-152. Furthermore, this study recommended the potential application of HOTAIR in GC immunotherapy for better prognosis and improved survival.