Postradiation caries is usually prevented by the application of topical fluorides (F) at high concentrations. The aim of this study was to develop an optimal preventive program for postradiation caries by evaluating the effects of F concentration and application procedures in subjects with radiation-related xerostomia. Six ground enamel slabs were mounted on each side of the lower denture of each of 7 xerostomia patients. Four procedures were used: no F exposure (control), neutral F gel applied every 2nd day or weekly, and a daily rinse with a F mouthwash for a period of 6 weeks. The enamel slabs were analyzed at weekly intervals by scanning optical monitoring, longitudinal microradiography, and scanning electron microscopy. In addition, hardness measurements were performed on the slabs. F analyses of the enamel slabs were done prior to their insertion in the appliances and after 6 weeks of intraoral exposure. In the control experiments severe demineralization of enamel occurred within 6 weeks. Application of F gel or the use of the F mouthrinse resulted in a significant inhibition of the demineralization process. Of the procedures evaluated, F gel applied every 2nd day was the most effective in preventing the onset of postradiation caries.