Objective  This study aims to investigate the expression profile and regulatory effect on cell proliferation of circular RNA(circRNA) in rat liver regeneration(LR).    Methods  CircRNA expression profile during rat LR of 114 rats’regenerating liver which induced by 2/3 partial hepatectomy was detected by high-throughput sequencing. MiRanda and TargetScan were performed to predict their target microRNA(miRNAs) and mRNAs. Gene Ontology(GO) and IPA were used to analyze the physiological activities and signaling pathways they involved. Cytoscape v3.0.2 was used to construct the interaction network. Finally, the candidate key circRNAs were selected by the expression pattern combining with the number and function of target miRNAs.    Results  20 878 circRNAs were detected during rat LR, among which 560 of them were differentially expressed, and 126 of them could bind to 117 target miRNAs, which were in turn to regulate 6510 downstream target mRNAs. They were involved in cell proliferation, stress response, substance metabolism and transforming growth factor-β(TGF-β), protein kinase A(PKA), Wnt/beta-catenin signaling pathways. 6 differential expressed circRNAs, including circRNA_03651, circRNA_03653, circRNA_04500, circRNA_05865, circRNA_11274 and circRNA_13559 might play a pivotal role in cell proliferation involved in rat LR by regulating 12 miRNAs and 15 mRNAs. Resultsing they were regarded as the candidate key circRNAs of rat LR.    Conclusion  560 circRNAs were differentially expressed in rat LR, among which circRNA_03651, circRNA_03653, circRNA_04500, circRNA_05865, circRNA_11274 and circRNA_13559 might play a crucial role on cell proliferation involved in rat LR via 12 miRNAs-15 mRNAs axis.