Background: Homeobox transcript antisense intergenic RNA (HOTAIR), a long noncoding RNA, has been reported to associate with the prognosis of patients with hepatocellular carcinoma (HCC) in several studies, however, the definite conclusion has not been obtained for conflicting results across different studies. The aim of this study is to determine the association of HOTAIR expression with overall survival, progression-free survival, and clinical features in HCC.Methods: PubMed, Cochrane Library, and Embase will be comprehensively searched to seek the relevant studies. The studies meeting the inclusion criteria will be included into this systematic review and meta-analysis. A combination of hazard ratio and 95% confidence interval is used to estimate the impact of HOTAIR expression on the overall survival and progression-free survival in HCC. The relationship between HOTAIR expression and clinical features of HCC is evaluated using the odds ratio and 95% confidence interval. The study quality is evaluated with the "risk of bias assessment" tool in Cochrane System Assessment Manual or Newcastle-Ottawa Scale. The subgroup analysis, publication bias, and sensitivity analysis are performed.Results: This study provides a strict and classic protocol for systematic review and meta-analysis to determine the prognostic significance of HOTAIR expression in HCC. The findings of this systematic review and meta-analysis may provide a novel diagnostic indicator and potential therapeutic target of HCC.Ethics and dissemination: This study is only a protocol for systematic review and meta-analysis, and all data used in this study is acquired through published studies. Therefore, the ethical review is not needed for this study.