Objective To investigate the expression and subcellular localization of long non-coding RNA (lncRNA)COL11A1-208, as well as the effect on the proliferation and invasion of oral squamous cell carcinoma (OSCC) cells. Methods The differential expression of COL11A1-208 in seven OSCC cell lines compared with primary cultured normal oral epithelial cells was detected by quantitative real-time PCR (qPCR), and the subcellular localization of COL11A1-208 was evaluated by cell nuclear/cytoplasmic fractionation and fluorescence in situ hybridization (FISH). CAL27 and HN4 cells were respectively transfected with COL11A1-208 Smart Silencer (SS-COL11A1-208 group) and negative control (NC) Smart Silencer (SS-NC group), while HN4 and HN6 cells were stably infected by COL11A1-208 lentivirus overexpression vector (LV-COL11A1-208 group) and NC lentivirus overexpression vector (LV-NC group). Cell proliferation in each group was detected by CCK-8 assay and plate colony formation assay, while cell migration and invasion ability in each group were detected by Transwell assays. Then, the expression of COL11A1 were detected by qPCR and Western blotting assays, while the protein expression of E-cadherin and vimentin was detected by Western blotting assay. Finally, the effect of COL11A1-208 on OSCC cells in vivo was studied by xenograft formation assay. Results COL11A1-208 was highly expressed in OSCC cell lines compared with the normal cells (P<0.05). The results of nuclear and cytoplasmic RNA isolation assay showed that the nuclear proportion of COL11A1-208 in CAL27, HN4 and HN6 cells was significantly higher than that in cytoplasm (P<0.01); similarly, FISH results showed that COL11A1-208 was primarily localized within the nucleus of OSCC cells. The relative expression of COL11A1-208 in SS-COL11A1-208 group was significantly lower than that in the SS-NC group (CAL27: 0.225±0.030 vs. 1.000±0.000; HN4: 0.393±0.028 vs. 1.000±0.000; P<0.01). Compared with the SS-NC group, proliferation activity, colonizing ability, migration and invasion abilities of SS-COL11A1-208 group decreased significantly (P<0.05). The relative expression of COL11A1-208 in LV-COL11A1-208 group was significantly higher than that in the LV-NC group (HN6: 6524.216±3395.926 vs. 1.000±0.000; HN4: 3486.230±743.908 vs. 1.000±0.000; P<0.05).Compared with the LV-NC group, proliferation activity, colonizing ability, migration and invasion abilities of LV-COL11A1-208 group were significantly increased (P<0.05). Compared with the SS-NC group, the relative expression of COL11A1 protein in SS-COL11A1-208 group decreased significantly (P<0.05), while the relative expression of COL11A1 protein in LV-COL11A1-208 group increased significantly than that in the LV-NC group (P<0.01). In addition, compared with the SS-NC group, the relative expression of E-cadherin in SS-COL11A1-208 group increased significantly (P<0.05), and the relative expression of vimentin decreased significantly (P<0.05). In LV-COL11A1-208 group, the relative expression of E-cadherin decreased significantly (P<0.05),and the relative expression of vimentin increased significantly (P<0.01). In vivo experiments showed that the xenograft tumor weight and volume of ASO-COL11A1-208 group were significantly reduced (P<0.05), while the xenograft weight and volume of LV-COL11A1-208 group were significantly enhanced (P<0.05). Conclusion COL11A1-208 could facilitate the cell proliferation and invasion of OSCC, which plays an important role in the development and progression of OSCCs.