Osteopontin is a tumor-associated protein that promotes tumor development and metastasis. The preoperative blood samples of 94 oral squamous cell carcinoma (OSCC) patients and 28 healthy individuals were analyzed for plasma osteopontin levels, and another 256 paraffin-embedded OSCC specimens were analyzed by osteopontin immunostaining. The patients with advanced tumor (T) stage (T3/T4 vs. T1/T2) and positive nodal (N) status had significantly higher plasma levels of osteopontin (both p<0.001). Positive osteopontin immunostaining also correlated significantly with advanced T stage (p<0.001), positive N status (p<0.001), advanced TNM stage (p<0.001) and male gender (p=0.016). Unfavorable cumulative 5-year overall survival rates correlated significantly with positive osteopontin immunostaining (p<0.001), advanced T stage (p<0.001), positive N status (p<0.001) and advanced TNM stage (p<0.001). However, Cox regression analysis revealed that T stage and N status were independent prognostic factors for survival (both p<0.001) and osteopontin immunostaining was marginally significant for survival (p=0.056). The present study demonstrated that high expression level of osteopontin in either the plasma or the tumor of the patients with OSCC was associated with tumor progression, suggesting that osteopontin expression is an important prognostic factor for OSCC.