OBJECTIVE Fixed orthodontic appliances impair oral hygiene increasing the risk of non-cavitated lesions (NCLs) and tooth decay. The aim of this study was to compare the outcomes of fluoride and xylitol varnishes in preventing NCLs during comprehensive orthodontic treatment. METHODS The sample comprised 55 volunteers from 15 to 20 years of age under orthodontic treatment that were randomly divided into three groups: Fluoride Group (FG; n=17), Xylitol Group (XG; n=19), and Placebo Group (PG; n=19). The patients in each group received two applications of the following varnishes: DuraphatTM (5% NaF), 20% xylitol, and placebo (no F/Xylitol) in the three groups, respectively. The varnishes were applied in the first appointment (T0) and 3 months later (T1). Clinical examinations were carried out at T0 and 6 months after (T2) using the ICDAS index and the QLF system (fluorescence difference). The intergroup comparisons were performed by ANOVA/Tukey's or Kruskal-Wallis/Dunn's tests (P<0.05). RESULTS There was no significant intergroup difference regarding ICDAS index changes from T0 to T2. Fluoride varnish produced significantly greater increase in fluorescence of NCLs (mean change of -0.65 +0.78 and -0.56 +0.83, for maxilla and mandible, respectively) in comparison to the other groups. The majority of non-cavitated lesions improved in the fluoride and xylitol varnish groups. CONCLUSIONS Fluoride varnish produced significantly greater increase in enamel fluorescence compared to xylitol and placebo varnishes. In short term, both fluoride and xylitol varnishes produced remineralization of NCLs in orthodontic patients. CONCLUSIONS Non-cavitated lesions can be effectively controlled in high-risk orthodontic patients by means of fluoride varnishes. BACKGROUND ReBEC Identifier: RBR-6mdxfq; Date of Register: March 19th, 2020. Retrospectively Registered.