Studies have found that circRnA in exosomes is associated with oral squamous cell carcinoma (oScc) progression. In this study, we examined the expression of circ_0000199 in circulating exosomes from patients with oScc and its role in the evaluation of relapse and prognosis. Real-time quantitative reverse transcription-polymerase chain reaction was performed to assess circ_0000199 expression in circulating exosomes from 108 patients with OSCC and 50 healthy people. Gain-and loss-functional experiments were performed to assess the role of circ_0000199 on cell proliferation and apoptosis in OSCC cells. Our results showed that the high level of circ_0000199 in circulating exosomes was significantly associated with betel quid chewing, tumor size, lymphatic metastasis, and TNM stage in patients with OSCC. In addition, the patients with high exosomal circ_0000199 had higher tumor recurrence rate and higher mortality rate than the patients with low exosomal circ_0000199. Overexpression of circ_0000199 promoted, while knockdown of circ_0000199 inhibited OSCC cell growth. Bioinformatics analysis predicted that circ_0000199 interacted with miR-145-5p and miR-29b-3p simultaneously, which were involved in multiple tumor-related signaling pathways. in conclusion, upregulation of circ_0000199 in circulating exosomes from patients with OSCC is positively associated with poor survival outcome. Circulating exosomal circ_0000199 can be used as a biomarker and potential therapeutic target for oScc. Oral squamous cell carcinoma (OSCC) is one of the most common malignant tumors in the world, accounting for 3% of malignant tumors 1. Although the treatment of OSCC has made breakthroughs in the past decades, the 5-year mortality rate is still less than 50% 2. Early diagnosis and early treatment are the keys to improve the survival rate of patients with OSCC. Exosomes have phospholipid bilayer membrane with the markers TSG101 and CD63. The size of exosomes ranges from 30 to 100 nm. These vesicles exist in almost all body fluids of the human body, including blood, serum, saliva, cerebrospinal fluid, and urine 3. Exosomes contain various substances, such as proteins, DNA, microRNA (miRNA), circular RNA (circRNA). These molecules can be transported to regulate the signaling pathways of the recipient cells 4. CircRNAs are covalently formed from the ends of a single RNA molecule, without 5′ and 3′ ribonucleotide end, and circRNAs are expressed abundantly, conserved and stably in cells with temporal and spatial specificity 5. CircRNAs can bind to miRNAs to inhibit their functions. Therefore, circRNA is also called miRNA sponge. With the continuous understanding of circRNA, researchers have found that circRNAs are widely involved in the occurrence and development of physiology and disease as well as tumors 6. As a new type of regulatory endogenous RNA, circRNAs are expected to become a tumor diagnostic marker and therapeutic target due to its characteristics such as stability, conservation, and tissue-specific expression 7. For example, circRNA_...