Objectives: In oral squamous cell carcinoma (OSCC), cyclooxygenases (COX-1 and COX-2) contribute to inflammation, and cluster of differentiation factor 147 (CD147) contributes to invasiveness, but their relationship has not been previously examined within a cohort of patients with OSCC or OSCC cell lines. Study Design: COX-2 and CD147 expression was determined by using immunohistochemistry on 39 surgical biopsy specimens of OSCC. Expression in tumor cells, stroma, and adjacent oral epithelium was characterized by using a visual grading system. COX-1, COX-2, and CD147 expression was determined in vitro by using OSCC cell lines (SCC25, BHY, and HN) and reverse transcriptase-quantitative polymerase chain reaction. Secretion of prostagladin E2 (PGE2) from OSCC cell lines was determined by using PGE2 enzyme-linked immunosorbent assay. Results: Biopsy specimens showed higher COX-2 expression in tumor cells compared with stroma and adjacent epithelium (P < .05). There was no difference in CD147 expression among the tumor cells, stroma, and adjacent epithelium. In OSCC cell lines, there was a trend for COX-2 and CD147 gene expression to be coordinated. Interestingly, PGE2 secretion was more closely related to COX-1 expression than to COX-2 expression. Conclusions: COX-1, COX-2, and CD147 appear to be independently regulated in OSCC, potentially representing 2 therapeutic targets for future investigation. COX-1 expression in OSCC deserves further study because it may be an important determinant of PGE2 secretion from OSCC cells.