Background: The improved understanding of cancer-specific oncoproteins could lead to the development of new biomarkers or therapeutic strategies for oral cancers. Methods: We conducted this study as follows: i) Identification of up-regulated genes in oral cancers by means of cDNA microarray, ii) Validation of clinicopathological significance of their protein expression by tissue microarray, iii) Examination of the growth on cancer cells by siRNA, iv) Elucidation of their biological effects on tumor growth. Results: We selected a secreted protein, OASEP1 (oral cancer-associated serum protein 1) as a candidate. Immunohistochemical staining showed that OASEP1 protein expression in cytoplasm was observed in 73 (74.4%) of 98 oral cancers that had undergone curative surgery. In addition, high level of OASEP1 expression was associated with poor prognosis for oral cancer patients (P = 0.0158, by log-rank test). Suppression of OASEP1 expression by siRNA for OASEP1 significantly suppressed the growth of oral cancer cell lines partly through apoptosis as detected by flow cytometric analysis, apoptosis assays, and time lapse imaging. In addition, siRNAs for a candidate receptor of OASEP1 also significantly inhibited its expression and the growth of oral cancer cells, indicating that the functional interaction between OASEP1 and its receptor could regulate the growth of oral cancer cells. Conclusions: Our data suggest that OASEP1 is a possible prognostic biomarker and therapeutic target for oral cancer.