Leukoplakia in the oral cavity has been used as a putative surrogate marker of head and neck cancer development. A class of chemoprevention compounds, called protease inhibitors, has been shown in vitro and in animal models to effectively suppress premalignant lesions. Bowman-Birk inhibitor (BBI) is a protease inhibitor derived from soybeans that has demonstrated chemoprevention activity in many in vitro and animal systems, including the hamster cheek pouch model. Pilot, Phase I and Phase IIa studies of Bowman-Birk Inhibitor in patients with oral leukoplakia have demonstrated no detectable side effects. In the Phase IIa trial, changes in the protease activity in oral mucosal cells after BBI Concentratec (BBIC) treatment correlated with the changes in neu protein levels. Additionally, evidence for a dose-related treatment effect of BBIC on oral leukoplakia was demonstrated. These results indicate that BBIC should be investigated for chemopreventive activity in a randomized clinical trial.