Purpose: The rate of tonsil oropharyngeal cancers is increasing. MicroRNAs (miRNAs) are identified as small, noncoding, endogenously expressed RNAs that target mRNAs and regulate the post-transcriptional levels of protein expression. MiRNA-21(miR-21) is significantly increased in patients with oral carcinoma and has oncogenic roles in oral carcinogenesis. Therefore, miRNAs have been recommended to be used in the early diagnosis of HNC.Methods - rt-qPCR was utilized to evaluate the expression levels of human salivary miR-21. Samples were collected from individuals diagnosed with tonsil squamous cell carcinoma (TSCC) (n = 45) in both whole saliva and supernatant saliva. Then these levels were compared to those of a control cohort consisting of healthy individuals (n = 45) to determine differential expression patterns.Results- Salivary miR-21 displayed a notable elevation in all stages of tonsil squamous cell carcinoma (TSCC), including cases involving small tumors. The initial analysis revealed a significant up-regulation of both whole saliva and salivary miR-21 of the supernatant in patients with TSCC compared to controls (P= 0.01, 0.02 respectively). Furthermore, miR-21 showed a higher abundance in whole saliva in contrast to its levels in supernatant saliva. These observations confirm the potential of salivary miR-21 for the detection of tonsil malignancies.Conclusions This investigation underscores the ability of salivary miR-21 for the detection and ongoing prognostic monitoring of tonsil squamous cell carcinoma (TSCC), both in whole saliva and in supernatant saliva samples.