INTRODUCTION: The demineralization of enamel adjacent to orthodontic brackets is a significant clinical problem. The purpose of this in-vitro study was to investigate the effect of sodium fluoride (Colgate Neutrafluor 9000 ppm) (NaF) and 10% casein phosphopeptide-amorphous calcium phosphate (GC Tooth Mousse) (TM) on enamel demineralization adjacent to orthodontic brackets. METHODS: Forty specimens were sectioned from the buccal or lingual surfaces of extracted sound third molars. Twenty specimens had molar tubes bonded with composite resin (Transbond XT, 3M, St Paul, Minn) (CR), and 20 were bonded with resin-modified glass ionomer cement (Fuji Ortho LC, GC America, Alsip, Ill) (RMGIC). A 2-mm window for enamel demineralization was prepared. The specimens were randomly divided into 4 treatment groups: control, TM, TM/NaF (50/50 w/w), and NaF. The treatment solutions were placed around the bracket margins, and the specimens were immersed inverted into a carbopol demineralization solution at 37 degrees C. The enamel specimens were exposed for 96 hours, with the demineralization and topical solutions changed every 4 hours. Quantitative light-induced fluorescence (QLF) images were taken every 8 hours under controlled conditions. The difference in fluorescence (DeltaF) and the proportional DeltaF (%F) change between baseline and 96 hours was calculated. RESULTS: RMGIC significantly reduced DeltaF and %F when compared with CR (ANOVA, P = .029 and P = .034, respectively). Application of TM with CR, NaF with CR, and TM/NaF with CR significantly reduced DeltaF and %F compared with the control CR (Tukey post-hoc test, P <.001). Application of TM/NaF with RMGIC significantly reduced DeltaF and %F compared with the control RMGIC (Tukey post-hoc test, P = .008, P = .019, respectively). CONCLUSIONS: With the limitations of any in-vitro study, the following clinical conclusions can be drawn. The use of RMGIC alone can significantly decrease enamel demineralization compared with CR. The application of TM/NaF can provide significant additional prevention of enamel demineralization when RMGIC is used for bonding. The application of TM, NaF, or TM/NaF can significantly prevent enamel demineralization when CR is used for bonding. The use of both agents should be recommended for any at-risk orthodontic patient to provide preventive actions and potentially remineralize early (subclinical) enamel demineralization.