The aim of this study was to develop an in vivo model in which onset, progression, and prevention of xerostomia-related dental caries can be studied. The progress of the caries process was investigated on ground and polished human enamel blocks placed in the lower denture of 7 edentulous subjects suffering from xerostomia. During a period of 6 weeks the samples were analyzed at weekly intervals by means of scanning optical monitoring, scanning longitudinal microradiography, scanning electron microscopy, and hardness measurements. Although the indentation length increased significantly within 2 weeks, no demineralization could be yet observed with scanning optical monitoring, longitudinal microradiography, and electron microscopy in most samples. Starting from the 3rd week a progressive demineralization could be observed by all methods. The mineral loss (hydroxyapatite) in the 3rd week was 0.0126 kg.m-2 (median) which increased to 0.0761 kg.m-2 after 6 weeks. Scanning electron microscopy showed a destruction which resembled that of natural xerostomia-related dental caries. From this study it may be concluded that the in vivo model developed is suitable for studying onset, progression, and prevention of xerostomia-related dental caries.