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Purpose: Cancer stem cells (CSCs) constitute a distinctive subpopulation of cancer cells that are competent in tumor initiation, invasion, recurrence, and resistance to chemoradiotherapy. CD44, a hyaluronic acid (HA) receptor has been considered as a potential CSC marker in head and neck cancer. The purpose of this study is to evaluate the correlation between CD44 and clinicopathological parameters, treatment response, survival, and recurrence. Methods: The CD44 expression was examined by immunohistochemistry (IHC) in 90 samples of head and neck squamous cell carcinoma (HNSCC) confirmed patients. The expression of CD44 and its association with clinicopathological parameters, treatment response, and survival was determined. Results: In all HNSCC patient samples, CD44 was expressed consistently at different intensities. Tumor size (p < 0.001), stage (p < 0.001), and treatment response (p < 0.001) showed statistically significant association with CD44 expression. Alcohol and CD44 were observed as independent predictors of response to radiotherapy using multivariate ordinal logistic regression analysis. Analysis of 2‐year overall survival (OS) showed that CD44 expression (p = 0.02), tumor size (p = 0.001), lymph node status (p < 0.001), stage (p < 0.001), and grade (p = 0.007) were significantly associated with OS. Using Cox regression analysis, lymph node status (p = 0.001), grade (p < 0.001), recurrence (p < 0.001), and CD44 expression (p = 0.003) were found to be potential independent predictors of OS. Conclusion: Our findings suggest that CD44 contributes to resistance to radiotherapy and poor OS. The results also suggest that except for CD44 there could be other factors such as lymph node metastasis, grade, and alcohol which should be investigated as potential targets for therapy. [ABSTRACT FROM AUTHOR]