Introduction: One of the most common cancers of the oral cavity is oral squamous cell carcinoma (OSCC). Previous studies have provided evidence that apolipoprotein C-I (Apo C-I) has an oncogenic role beyond its classical function. Although it has been investigated in prostate, breast, and lung cancer, there is no information available regarding Apo C-I expression in tumor and pri-tumor tissues of OSCC patients. Thus, the goal of the present study was to unravel the expression of Apo C-I in OSCC and investigate its correlation with the survival and grade of OSCC patients. Methods: The Apo C-I mRNA level was measured in tumor and pri-tumor tissues of 16 OSCC patients. In addition, the 34 paraffin-embedded tissues of OSCC patients and IHC technique were used to analyze the association of Apo C-I protein with the survival of OSCC patients. Results: The mRNA (P=0.0386) gene expression of Apo C-I showed a statistically significant difference between tumor and pri-tumor tissues of OSCC patients. It seems that a high protein level of Apo C-I is related with poor survival of OSCC patients (P=0.04). The Apo C-I protein was positively correlated with the tumor site (Pearson r= 0.485, P=0.0036) but not the grade (Pearson r= 0.2295, P=0.1917). Our data showed that high Apo C-I protein levels might be correlated with poor survival of OSCC patients. Conclusion: Our findings suggest that patients with high protein levels of Apo C-I may have lower survival, making it a potential prognostic factor for OSCC. However, further investigation is necessary to establish this concept.