Oral squamous cell carcinoma (OSCC) is the most common head and neck malignancy. Here, we evaluated the expression of cold-inducible RNA-binding protein (CIRP) and toll-like receptors 4 (TLR4) in OSCC tissues with immunohistochemistry. Using biostatistical methods designed to assess the impact of the expression of CIRP and TLR4 on the prognosis of patients with OSCC and relate that expression to the clinicopathological characteristics of these patients. For the first time, we demonstrated that the expression of CIRP and TLR4 was increased in OSCC and that high levels of CIRP or TLR4 expression were associated with a short survival rate. In addition, we were surprised to find that the levels of expression of CIRP and TLR4 were very similar. The goal of this study was to evaluate whether these two genes may provide clues as to the regulatory mechanisms of OSCC, serve as prognostic markers and establish a new direction for further studies of these biological mechanisms.