Although it is known that innate immunity is important for protecting the body against foreign agents such as bacteria, little is known about elements of the innate immune system that have antitumor activity. This prospective study was designed to investigate the function of human beta-defensin 3 (hBD-3), an important component of the innate immune response, in oral squamous cell carcinoma (OSCC). Paired cancerous and noncancerous specimens of 45 patients who underwent surgical treatment for OSCC were examined for hBD-3 expression on protein and mRNA. Clinical and pathological features such as age, gender, tumor and lymph node status, UICC stage, and histological grading were correlated. hBD-3 was significantly overexpressed in tumors in comparison to healthy tissue examined with real-time quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) analysis (p = .004). Immunohistochemical stain for hBD-3 was much more pronounced in tumors than in corresponding healthy mucosa. The results illustrate that hBD-3 is frequently overexpressed in oral squamous cell carcinomas and seems to be related to oncogenesis. Increased expression of hBD-3 in oral squamous cell carcinomas suggests its potential role in the pathogenesis of oral cancer. This might be a starting point for novel pharmacological/molecular treatment modalities.