Calcium-fluoride-like deposits play a key role in caries prevention by topical fluoride. Previous microhardness analyses have introduced errors due to a substrate effect, and thereby could not substantiate the early loss of these deposits. To address this question, we applied Atomic Force Microscopy (AFM) and a nano-indentation technique in this study to characterize the nano-mechanical properties and topographic structure of enamel surfaces following topical fluoride treatment. The deposits were found to have a low nano-hardness and a high nano-wear depth, which explains the early loss of calcium-fluoride-like deposits. However, a 22% increase in the fluoride concentration could still be detected on the treated enamel surface following the removal of the surface deposits, justifying the long-term effectiveness of topical fluoride treatment.