Sealant application is a common strategy for preventing enamel demineralization during multibracket treatment. The aim of this study was to assess the efficacy in enamel demineralization prevention of two fluoride-containing enamel varnishes compared to a non-fluoride varnish, weekly fluoride gel application, and a non-treated control group. Enamel specimens obtained from 75 human upper permanent incisors were randomly allocated to five trial groups (each n = 15): A), ProSeal (Reliance), B), Maximum CureA (R) (Reliance), C), CervitecPlus (Ivoclar Vivadent, Schaan, Liechtenstein), D) elmexA (R) gel,e (GABA, Lorrach, Germany), and E), a non-treated control group. Groups A-C received a baseline varnish application, whereas group D specimens received a once weekly gel application for 2 min. Six demineralization cycles per day were carried out for 5 min each using 0.05 M citric acid, with the specimens stored in remineralization solution between cycles. Lesion depth expressed in percentage fluorescence loss (Delta-F in %) compared to baseline (T0) was assessed quantitatively with light-induced fluorescence (QLF) after 3 (T1), 7 (T2), 14 (T3), and 30 (T4) days globally and for each time point, and analyzed for compounds using the Kruskal-Wallis test (alpha = 5%), and additional one-sample Wilcoxon tests for each time/compound combination (Bonferroni-corrected alpha-levels alpha* = 0.05/4 = 0.0125). Significant fluorescence loss revealing greater lesion depth was detected in the untreated controls (E) at T3, and in groups A (ProSeal) and C (CervitecPlus) at T4. No significant Delta-F changes were seen in the specimens from groups B (Maximum CureA (R)) and D (elmexA (R) gel,e). Maximum CureA (R) sealant seems to offer efficient protection against demineralization during fixed orthodontic treatment, as does weekly application of elmexA (R) fluoride gel.