The anti-cariogenic properties of three fluoride-releasing materials on root surfaces were evaluated using two different caries models. Standardized cavities were prepared in dentin specimens and restored with either glass-ionomer, resin-modified glass-ionomer, polyacid-modified resin composite or resin composite material. Two groups of 56 specimens were demineralized using a microbial caries model for three days, while another 56 specimens were demineralized using a chemical demineralization model for three days. Lesions around the restorations were measured with a confocal laser scanning microscope. Glass ionomers demonstrated significant anti-cariogenic properties when exposed to the chemical model. However, no significant anti-cariogenic properties were observed with the microbial caries model. In conclusion, the fluoride releasing materials showed different anti-cariogenic properties in root surfaces under the different caries models, suggesting that caution should be exercised when trying to extrapolate the results of in vitro studies to the clinical situation.