The aim of this study was to compare the caries preventive effect of highly fluoridated dentifrices and gels on sound dentin as well as on artificial dentin caries-like lesions.Bovine dentin specimens (n = 240), with 2 different surfaces each (1 sound surface [sound treatment (ST)] and one caries lesion [demineralized treatment (DT)]), were prepared and randomly allocated to one highly (6 × 120 min demineralization/day [H]) and one lowly cariogenic (6 × 60 min demineralization/day [L]) pH-cycling model. Treatments during pH-cycling (28 days) were: brushing 2×/day with: 0 ppm F [H0/L0], 1,450 ppm F [H1,450/L1,450], 2,800 ppm F [H2,800/L2,800], 5,000 ppm F [H5,000/L5,000], 5,000 ppm F plus TCP [H5,000+TCP/L5,000+TCP], and 12,500 ppm F [H12,500/L12,500] containing dentifrices/gels. Dentifrice/gel slurries were prepared with deionized water (1:2 wt/wt). Differences in integrated mineral loss (∆∆Z) and ∆ lesion depth were calculated between values before and after pH-cycling using transversal microradiography.The correlation between ΔΔZDT and F- was strong for the highly (rH = 0.691; p < 0.001) and moderate (rL = 0.500; p < 0.001) for the lowly cariogenic model, indicating a fluoride dose-response for both. Significant differences for ΔΔZDT and ΔΔZST could be found between H0, H1,450, H5,000, and H12,500 as well as L0, L5,000, and L125,000 (p ≤ 0.046; analysis of covariance [ANCOVA]). Except for 0 ppm F-, no significant difference in ΔΔZST and ΔΔZDT could be found between the highly and lowly cariogenic model (p ≥ 0.056; ANCOVA).For both pH-cycling conditions a dose-response for fluoride could be revealed. For elderly people with exposed root surfaces, the use of gels containing 12,500 ppm F instead of regularly (1,450 ppm F) or highly (5,000 ppm F) fluoridated dentifrices should be further investigated, as it offered higher caries-preventive effects in vitro.