BACKGROUND The objective of this two-arm split-mouth randomized trial, was to evaluate the ability of fluoride-releasing resin composite to prevent demineralization and white spot lesion (WSL) formation, during orthodontic treatment with fixed appliances. METHODS Patients needing comprehensive orthodontic treatment were randomly allocated into two groups, according to the half split-mouth technique. This trial examined a total of 300 teeth in each group: the control group, in which brackets were fixed with a non-fluoride-containing adhesive resin; and the intervention group, in which brackets were fixed with a fluoride-containing adhesive resin. Eligibility criteria included Class I malocclusion in the permanent dentition, adequate oral hygiene and no missing teeth, active caries, enamel demineralization, fluorosis staining, or heavy restorations. The primary outcome was the formation of WSLs. Randomization was achieved using a computer-generated random number table; blinding of the patients, assessor, orthodontist and data analysist were achieved. The patients were followed for twelve months, during which time their teeth were checked every three months. To investigate the differences in frequencies and ranks of demineralization and WSL formation between the two groups, odds ratios were computed using mixed modelling (to compensate for the clustered nature of the data) with intervention as a fixed effect and patient as a random effect. RESULTS Thirty-four patients (ages, 13-25 years; mean age, 17.6) were randomized into a 1:1 ratio, though four patients dropped out before the start of the treatment. The percentage of the teeth showing the effects of demineralization and WSL formation, increased from 6.3% to 15% for the control group after three and twelve months, respectively, and from 3% to 16.3% for the study group, after three to twelve months, respectively. There were no significant differences between the two groups and no interaction between time and treatment group in the visual inspections (OR 0.79; 95% CI 0.52, 1.21), in DIAGNOdent examinations (OR 0.68; 95% CI 0.43, 1.06), or in photographic images (OR 0.72; 95% CI 0.46, 1.11). No serious harm was observed during the trial. CONCLUSIONS This trial was a single-centre trial, and treatment was carried out by one orthodontist. CONCLUSIONS Fluoride-containing resin adhesive does not have the desired preventive effect to prevent demineralization and WSL formation, during orthodontic treatment with fixed appliance. This randomized trial was not registered, and the protocol was not published before patient recruitment. BACKGROUND The University of Damascus funded this trial.