Aims: It is important to investigate the better prognostic markers of hepatocellular carcinoma (HCC) to improve the clinical management of HCC patients. Tumor-derived exosomes contain tumor-specific non-coding RNAs and having an emerging role in tumor progression and metastasis. Therefore, we determined the prognostic relevancies of two noninvasive circulating exosomal noncoding RNAs (miRNA-21, lncRNA-ATB) for HCC. Methods: HCC patients between October 2014 and September 2015 at Kyungpook National University Hospital, Daegu, South Korea were enrolled for this prospective study. Exosome was isolated by using ExoQuick (System Biosciences). In isolated exosome, exosomal RNA was extracted using miRNeasy serum/plasma kit (Qiagen). Cox regression analysis was used to identify independent predictors of HCC prognostic factors. Results: A total of 79 patients were enrolled in this study. During the study period, disease progression and mortality were found in 44 and 34 patients, respectively. Both miRNA-21 and lncRNA-ATB were successfully detected in the HCC serum sample. Both miRNA-21 and lncRNA-ATB were related to TNM stage and other multiple prognostic factors including T stage and portal vein thrombosis. However, they were not associated with age, gender, presence of cirrhosis, and etiology. In multivariate analysis, both higher miRNA-21 and higher lncRNA-ATB were identified as independent predictors of mortality and disease progression, along with larger tumor size and higher CRP (all P<0.05). The overall survival of HCC patients with a low miRNA-21 expression group (miRNA-21 < 0.09) was significantly higher than in patients with a high miRNA-21 expression group (miRNA-21 >0.09) (log-rank test: P=0.014). The overall survival was also significantly higher in patients with a low lncRNA-ATB expression group (lncRNA-ATB < 0.0016) than in patients with a high lncRNA-ATB expression group (lncRNA-ATB >0.0016) (log-rank test : P=0.005). Conclusions: This study provides strong evidence that circulating exo-somal non-coding RNAs (miRNA-21, lncRNA-ATB) may be novel prognostic markers and therapeutic targets for HCC.