Many genetic factors have been implicated in the development of oral squamous cell carcinoma (OSCC). Although mutations associated with OSCC have been well documented, the rate of these mutations is known to vary by location. The goal of this study was to determine the frequency of RAS, BRAF, PIK3CA, and TP53 mutations in OSCC within the Taiwanese population.A total of 79 OSCC tissue specimens were screened for the presence of RAS, BRAF, PIK3CA, and TP53 mutations.Missense mutations in HRAS were found in 10 of 79 cases (12.66%), and were significantly associated with tumor grade. PIK3CA mutations were observed in 11 of 79 cases (13.92%), including a rare mutation, Q546 P, that had not previously been reported in OSCC. TP53 mutations were observed in 26 of 79 patients (32.91%) and were significantly correlated with poor survival.The results suggest that HRAS, PIK3CA, and TP53 may play a role in OSCC tumorigenesis.