Head and neck cancer is the sixth most common cancer in the world and most of them are squamous cell carcinomas. High frequency of cisplatin resistance in head and neck squamous cell carcinoma (HNSCC) leads to tumor relapse and irresponsiveness to cisplatin-based chemotherapy. However, the mechanisms underlying cisplatin resistance is still largely unrevealed. In this study, we found that CD147 was overexpressed in cisplatin-resistant HNSCC cell lines. Based on the result, CD147 expression was down-regulated in the cisplatin-resistant cell line and we observed that the sensitivity to cisplatin increased, as showed in the results of MTT assay and PI-staining apoptotic detection. Meanwhile, transfection of CD147 expression vector promoted the occurrence of cisplatin resistance in the cisplatin-sensitive cell line. Simultaneously blocking of uPAR with neutralizing antibody would significantly prevent the occurrence of cisplatin resistance induced by CD147 overexpression. In conclusion, our study finds that CD147 is also involved in mediating cisplatin resistance in HNSCC and uPAR serves as a possible candidate that collaborates with CD147 in this process.