Objective: To investigate the mechanism of drug resistance in oral and maxillofacial carcinoma to chemotherapy. Materials and Methods: Forty cases of squamous carcinoma in the oral and maxillofacial region were examined for the multidrug resistance gene product P-glycoprotein using a monoclonal antibody, MRK16. Result: P-glycoprotein was detected in 62.5% of all samples. P-glycoprotein expression was related to the chemotherapy and the differentiation of carcinoma. P-glycoprotein expression was higher in the post-chemotherapy group than in the non-chemotherapy group (P < 0.05). Well-differentiated tumors expressed P-glycoprotein more frequently (P < 0.05). P-glycoprotein expression was compared with clinical response to chemotherapy. The accuracy rate of prediction was 75%. Conclusion: P-glycoprotein plays an important role in mechanism of drug resistance of squamous cell carcinoma in the oral and maxillofacial region.