Abstract More than 90% of oral cancer is histopathologically squamous cell carcinoma (SCC). According to its clinical behavior and histopathological features, we hypothesize that oral SCC can originate from either oral squamous epithelium or the minor salivary glands. In this study, we attempted to clarify the possibility of some oral SCC originating from the minor salivary glands, and to investigate whether these tumors showed particularly aggressive biological behavior. The mRNA expression profile of samples obtained from 6 patients with SCC of the oral floor (5 men, 1 woman; mean age 62.7 years) was analyzed by microarray containing 32,878 genes. Clustering analysis of the expression level of the 845 genes that were differentially expressed in normal oral squamous epithelium and normal salivary glands revealed that the 6 samples can be divided into 2 groups. The expression profile in four cases was similar to that of normal oral squamous epithelium, and in two cases was similar to that of normal salivary glands. Furthermore, we identified nine genes that reveal the origin of the oral SCC. Subsequently, we examined the expression levels of these 9 marker genes by reverse transcriptase-polymerase chain reaction to determine the origin of 66 oral SCCs. Twelve of the 66 oral SCCs were considered to originate from minor salivary glands, and these tumors showed high metastatic potential (p<0.05) and poor event free survival rate (p<0.05). In conclusion, determination of the origin of the oral SCC is helpful when making a treatment plan for patients with oral SCC. Citation Format: Makoto Kinouchi, Sayaka Izumi, Daisuke Uchida, Nobuyuki Kuribayashi, Yuske Komiyama, Shuji Tsuchida, Atsushi Fujita, Hitoshi Kawamata. Determination of the origin of oral squamous cell carcinoma by microarray analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1551.