To date, microRNA-21 (miR-21) has been reported to be associated with the prognosis of hepatocellular carcinoma (HCC) in various studies, yet the results were inconsistent. The purpose of this two-part study, consisting of a retrospective cohort study and a meta-analysis, sets out to determine the prognostic role of miR-21 expression among HCC patients who underwent surgical resection. Methods. In this study, we first detected miR-21 expression in HCC patients by quantitative real-time PCR (qRT-PCR). Patients were divided into a high miR-21 expression group and a low miR-21 expression group according to the median level of miR-21 expression in tumor tissues. The survival outcomes of the two groups were analyzed by the Kaplan-Meier method with the log-rank test. Multivariate analysis of the prognostic factors was performed with the Cox regression model. Subsequently, eligible studies were obtained by searching on PubMed, Cochrane Library, and Web of Science, and a meta-analysis was performed to assess the prognostic role of miR-21 expression among HCC. The qRT-PCR analysis results of our cohort study showed miR-21 expression was significantly upregulated in HCC tissues when compared with adjacent nontumor tissues. Multivariate analysis suggested that miR-21 expression was an independent prognostic factor for overall survival (OS) (hazard ratio, HR = 2.361) and disease-free survival (DFS) (HR = 2.024) in HCC patients who underwent surgical resection. A total of 10 studies with 969 patients were enrolled in the meta-analysis, consisting of 9 studies from the database search and our cohort study. We observed that elevated miR-21 expression can predict poor OS (HR = 2.24, 95%CI = 1.73-2.91, P < 0.001) and DFS/recurrence-free survival (RFS) (HR = 2.44, 95%CI = 1.62-3.67, P < 0.001) in surgically resected HCC patients. Our study demonstrated that miR-21 high expression among surgically resected HCC patients is a prognostic factor that indicated adverse survival. Copyright © 2020 Xujian Huang et al.