The aqueous solubility of triclosan is only about 10 microg/mL. This very low solubility can hamper its biological activity in the oral cavity, which could explain the mixed clinical results obtained from triclosan toothpaste trials. Triclosan availability in a silica-based toothpaste was improved through cyclodextrin solubilization. The triclosan in vivo availability was optimized through a series of phase-solubility studies and triclosan release studies. It was found that in toothpastes, natural beta-cyclodextrin (betaCD) was just as good a solubilizer as the more water-soluble betaCD derivatives. Furthermore, the amount of cyclodextrin could be reduced by as much as 60% through the addition of a small amount of carboxymethylcellulose (CMC), without affecting triclosan release from the toothpaste. Optimally, cyclodextrins resulted in an almost 3-fold enhancement of triclosan availability compared to an identical toothpaste containing no cyclodextrin. In vivo studies in humans showed that replacing triclosan with triclosan/betaCD in the toothpaste resulted in only moderate improvement in triclosan substantivity. However, replacing triclosan with triclosan/betaCD/CMC complex resulted in significant improvement in triclosan substantivity. Furthermore, the in vivo studies showed that replacing free triclosan with triclosan/betaCD/CMC complex resulted in an almost 3-fold increase in initial triclosan concentration in saliva after brushing and about 2-fold increase in duration of activity.