Objective: To investigate the effect of a 5% sodium fluoride varnish with functionalized tri-calcium phosphate (fTCP) on post-orthodontic white spot lesions. A secondary aim was to study if the patients and their clinicians perceived clinical improvements. Method and materials: Fifty-nine patients with at least two visible WSLs on their maxillary incisors, canines, or first premolars present at the debonding of fixed appliances (baseline) were enrolled and assigned to a Varnish group (Clinpro White Varnish, 3M Espe) receiving topical applications at baseline and after 8 weeks, or a Control group treated with a fluoride-free mock product. The primary endpoint was white spot lesion appearance after 16 weeks, assessed from photographs using the modified ICDAS white spot lesion score (0 to 3). The patients and the dental examiners rated the white spot lesions subjectively with aid of a visual analog scale. Results: Fifty-seven patients completed the study. After 16 weeks, 62% of the white spot lesions in the Varnish group were completely reversed (score 0) compared to 39% in the Control group. The treatment effect was statistically significant (OR 0.22; 95% CI 0.08 to 0.59, P = .003) after adjusting for baseline oral hygiene index and type of tooth. A significant correlation (P .05) was observed between patients' and orthodontists' perception of the lesions. Conclusion: The 5% sodium fluoride varnish with fTCP appeared clinically effective in reversing post-orthodontic white spot lesions 16 weeks after debonding. The patients and the clinicians agreed on the obtained esthetic improvements. Keywords: adolescents, orthodontics, remineralization, secondary prevention, white spot lesion