Small ubiquitin-like modifiers (SUMOs) play an important role in tumors. The SUMOylation can be reversed by SUMO-specific proteases (SENPs). As one of the crucial members of the SUMO system, SENP5 is essential in mitosis and/or cytokinesis. In the present study, we analyzed the expression of SENP5 in human oral squamous cell carcinoma and investigated the relationship between its expression level and clinicopathological parameters. Expression levels of SENP5 in 48 patients with oral squamous cell carcinoma were investigated by immunohistochemistry. Immunoreactivity was evaluated semiquantitatively using German immunoreactive score (IRS). The relationship between SENP5 expression status and the clinical and pathological characteristics of patients was analyzed and survival curves were calculated using the Kaplan-Meier method and log-rank tests. We found that SENP5 predominantly localized to cytoplasm of OSCC cells and the expression of SENP5 in OSCC is not the same as in paracarcinoma epithelia. The SENP5 expression status was associated with differentiation of OSCC and not with any other clinicopathological parameters. These findings suggest altered subcellular localization of SENP5 in OSCC cells and the correlation between SENP5 expression and the differentiation of OSCC.