The aim of this in situ study was to compare the protective effect of TiF4, SnF2 and NaF on the development of erosion-like lesions in human enamel. Fourteen human molars were each divided into 4 specimens, mounted on acrylic mouth appliances and worn by 7 volunteers for 9 days. In order to mimic a feasible treatment procedure for patients with voluntary or involuntary gastric reflux, the specimens were etched for 2 min twice a day (0.01 M HCl) and fluoride applications were performed every third day (2 min). The controls were treated as the other specimens except for the fluoride applications. Etch depths and surface roughness changes (R(q)) were measured by white light interferometry. Compared with the control, TiF4 and SnF2 reduced the etching depth by 100% (p < 0.001) and 91% (p < 0.001), respectively, and both treatments resulted in an observable surface layer. NaF had no significant protective effect (p = 0.46). It can be concluded that although SnF2 provided significant protection for the enamel surfaces, TiF4 showed the best protection against acid attack, while NaF had no significant protective effect in this study.