Napsin A is an aspartic proteinase expressed in some types of carcinomas, such as lung adenocarcinomas and renal cell carcinomas but rarely in squamous cell carcinomas. No specific studies have been carried out focusing on napsin A antibody expression in oral squamous cell carcinomas (OSCC). The aim of this study was to investigate the reactivity of this antibody in primary OSCC. This retrospective study included 70 OSCC cases of which 31 (44.3%) presented metastasis involvement. Patient data, including age, gender, tumor location, histological grade, regional and distant metastasis, were collected. OSCC edge epithelium with intraepithelial neoplasia and healthy oral mucosa (n = 10) were included in the analysis. Sections of lung adenocarcinomas (n = 2) were used as the positive control and an immunohistochemical assay for napsin A was performed on all cases. Napsin A expression was negative in all 70 cases of OSCC, as well as in the intraepithelial neoplasia adjacent to the carcinoma area and in healthy oral mucosa epithelium. Metastatic neck lymph nodes and distant organs were also negative for napsin A. This study shows that napsin A is consistently not expressed in oral squamous cell carcinoma, or in metastatic sites of primary OSCC, intraepithelial neoplasia, and healthy oral mucosa.