Head and neck squamous cell carcinoma (HNSCC) means a group of cancers developed from the upper aerodigestive tract, and 90% of them are squamous cell carcinomas. HNSCC is the tenth most commonly diagnosed form of cancer in males worldwide, but it is the seventh most common cause of cancer-related death. The circadian clock regulates daily rhythmic variations in various physiologic processes including sleep and activity, appetite, hormone levels, metabolism, and gene expression. Many recent studies have demonstrated that the disruption of circadian rhythm is associated with cancer development and tumor progression, such as chronic myeloid leukemia, hepatocellular carcinoma, endometrial carcinoma, and breast cancer. However the direct links between aberrant circadian clock gene expression and human malignancies, including HNSCC, remain largely unknown. In this study, the expression profiles of nine circadian clock genes of cancer tissue and noncancerous part from 40 patients of HNSCC were investigated. The expression of PER1, PER2, PER3, CRY1, CRY2, CKIε, and BMAL1 showed significant downregulation in the cancer tissues (p < 0.005). Downregulated PER3, CRY2, and BMAL1 expression was correlated with more advanced cancer stages (p < 0.05). Downregulated PER3 and upregulated TIM expression correlated with larger tumor size (p < 0.05), and lower expression of PER3 correlated with deeper tumor invasion (p < 0.05). Poor survival was related to lower expression of PER1 (p < 0.05) and PER3 (p < 0.01). These results indicate a possible association of circadian clock gene, especially PER3, expression with the pathogenesis of HNSCC.