Circular RNAs (circRNAs) are new types of endogenous non-coding RNAs, which are identified to have critical regulatory roles in cancer biology. In this study, we aimed to find the abnormally expressed circRNAs in hepatocellular carcinoma (HCC) and investigate the function and mechanism of circRNAs in HCC progression. Upregulation of hsa_circ_0091581 was identified by RNA-sequencing and validated by quantitative real-time polymerase chain reaction (qRT-PCR). Hsa_circ_0091581 expression was correlated with tumor size, disease-free survial and overall survival of HCC patients. Functionally, hsa_circ_0091581 could promote the proliferation of HCC cells in vitro. Mechanism research showed that hsa_circ_0091581 promoted cell proliferation via hsa_circ_0091581/miR-526b/c-Myc axis in HCC cells. Also, the expression of hsa_circ_0091581 in HCC could be regulated by c-Myc. These results revealed that hsa_circ_0091581/miR-526b/c-Myc/hsa_circ_0091581 positive feedback loop plays a vital role in HCC progression and hsa_circ_0091581 may be a potential prognostic biomarker and therapeutic target for HCC.