Objective To investigate the value of serum MIR4435-2HG level in the diagnosis and prognosis of oral squamous cell carcinoma. Methods This study was a retrospective case-control study. Five hundred and eighteen samples of oral squamous carcinoma of patients with head and neck squamous cell carcinoma in the cancer genome atlas project (TCGA) database, with long noncoding RNA MIR4435-2HG expression. The median was the boundary, and the patients were divided into high expression group and low expression group, and the 5-year disease-free survival rate and overall survival rate of the two groups were compared. Serum samples from 82 patients with oral squamous cell carcinoma who were admitted to the Department of Oral and Maxillofacial Surgery, Affiliated Stomatology Hospital of Huzhou Univerisity from January 2012 to January 2015 were enrolled to verify the prognostic value of MIR4435-2HG. Bioinformatics is used to predict the biological processes involved in MIR4435-2HG. Use the SPSS 23.0 to set the optimal diagnostic and prognostic cutoff for the MIR4435-2HG. Results A total of 518 oral squamous carcinoma patients in the TCGA database showed that the 5-year overall survival rate of the MIR4435-2HG high expression group [43.2% (112/259)] was significanthy lower than that of the MIR4435-2HG low expression group [51.7% (134/259)] (P 0.05). The lymph node metastasis rate of the MIR4435-2HG high expression group was significantly higher than that of the low expression group [12.9% (8/62)] (P<0.05). The histological grade of the high expression group [80.0 % (16/20)] was significantly lower than that of the low expression group [24.2 % (15/62)] (χ2=20.030, P<0.05). The results of bioinformatics analysis indicated that the biological functions of MIR4435-2HG target gene were mainly enriched in protein metabolism, processing of rRNA in nucleolus and cytoplasm, SEMA4D induced cell migration process, and mitochondrial translation process. Conclusions Serum MIR4435-2HG can be used as a potential prognostic marker for oral squamous cell carcinoma. Key words: Oral sprays; Diagnosis; Prognosis; Biomarker