OBJECTIVE The aim of this in vitro study was to evaluate the role of highly fluoridated dentifrice on remineralization characteristics of lowly and highly pre-demineralized enamel artificial caries lesions. METHODS Bovine enamel specimens were prepared (pH 4.95; 21 days) and discriminated in either lowly [L] or highly [H] pre-demineralized artificial caries lesions. Specimens with a mean ΔZbaseline,L (95% CI) of 5120 (4995; 5245) vol.% × μm and a mean ΔZbaseline,H of 8187 (8036; 8339) vol.% × μm were selected and randomly allocated to 12 groups (n = 20). Treatments during pH-cycling (28 days; 6 × 60 min demineralization/day) were brushing 2×/day with fluoride-free (0 ppm F- [L0/H0]), 1100 ppm F- [L1100/H1100], 2800 ppm F- [L2800/H2800], 5000 ppm F- [L5000/H5000], 5000 ppm F- + glycerin [L5000 + glycerin/H5000 + glycerin], and 5000 ppm F- + TCP [L5000 + TCP/H5000 + TCP] containing dentifrices. Dentifrice slurries were prepared with deionized water (1:3wt/wt). After cycling specimens presenting lesion surface loss were discarded and for the remaining 202 specimens, transversal microradiographic (TMR) analyses (ΔZpH-cycle/LDpH-cycle) were performed again. Changes in mineral loss (ΔΔZ = ΔZbaseline - ΔZpH-cycle) and lesion depth (ΔLD = LDbaseline - LDpH-cycle) were calculated. RESULTS Significant differences for ΔΔZ could be found between L0, L1100, and L5000 as well as H0, H1100, and H2800/H5000 (p ≤ 0.01; ANCOVA). Except for 0 ppm F-, higher ΔΔZ could be found in highly compared with lowly demineralized specimens (p ≤ 0.004; ANCOVA). After pH-cycling, a second lesion front could only be observed in H5000 and H5000 + TCP. The correlation between ΔΔZ and F- was moderate for lowly and highly demineralized lesions (rL = 0.591; pL < 0.001; rH = 0.746; pH < 0.001), indicating a fluoride dose response for both. CONCLUSIONS For both baseline substrate conditions, a dose response for fluoride could be revealed. CONCLUSIONS Remineralization characteristics of enamel directly depended on baseline mineral loss.