The long non-coding RNA (lncRNA) HOTAIR is an oncogene, that has been reported to be aberrantly expressed in multiple types of malignant tumor tissues. However, its expression and association with synovial sarcoma (SS) remains unclear. The present study aimed to elucidate the expression level of HOTAIR in SS tissues and also identify its role. Reverse transcription-quantitative PCR was used to detect the expression level of HOTAIR and microRNA (miR)-126 in 54 tissue samples from patients with SS, in 10 tissue samples from synovium tissues of normal patients, and in SW982 cells. The protein expression level was measured using western blot analysis and cellular immunofluorescence. Cellular proliferation, invasion and migration were assessed using MTT, Transwell and wound healing assays, respectively. HOTAIR was expressed at high levels in SS tissues. In contrast, miR-126 was expressed at low levels in SS tissues, and was negatively correlated with HOTAIR expression. HOTAIR knockdown in SW982 cells inhibited cellular proliferation in vitro, but also significantly increased the ratio of cells in the G1/G0 phase of the cell cycle, and decreased the ratio of cells in the G2/S phase. In addition, HOTAIR knockdown inhibited the invasion and migration of the SW982 cells, as observed in the Transwell and wound healing assays. Furthermore, HOTAIR knockdown increased miR-126 expression level and decreased the expression level of stromal cell-derived factor-1 (SDF-1) at the protein level. On the other hand, while miR-126-mimic decreased the protein expression level of SDF-1, miR-126-inhibitor increased its expression level in SW982 cells. Notably, HOTAIR knockdown or SDF-1 knockout significantly decreased the protein expression levels of CDK1, CDK2, cyclin D1, MMP-9, vimentin and N-cadherin, and significantly increased the protein expression levels of p21, p53 and E-cadherin in SW982 cells. HOTAIR was highly expressed in SS tissues, wherein it could promote the proliferation, invasion and migration of SS cells by increasing the expression of SDF-1 via miR-126 inhibition. Copyright: © Feng et al.