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Design: Prospective, randomized, double-blind, multicenter clinical trial., Case Selection: Participants between 12 and 25 years old, who were generally healthy, with 2 or more white spot lesions on the labial surface of anterior dentition., Data Analysis: 79 patients who developed white spot lesions (WSL) on the labial surface of anterior teeth following orthodontic treatment were randomly assigned to 4 intervention groups. Group 1 received 5% sodium fluoride varnish every 6 months, the second group received CPP-ACP every 6 months, the third group was treated with resin infiltration at the initial visit followed by placebo every 6 months, and the final group which was the control group was coated with 1400 ppm fluoride toothpaste every 6 months. All the candidates were instructed to brush twice daily using a specific toothbrush and 1400 ppm fluoride toothpaste. The study lasted for 12 months, and photographs of the teeth with WSL were taken before and after completion of the intervention. Photographs were analyzed using ImageJ software to compare the changes in the percentage of WSL area to total tooth surface area among the four study groups. The distribution differences among groups were compared using nonparametric tests and differences between baseline and 1-year follow-up parameters were analyzed using paired chi-square tests., Results: Reduction in the area of WSL were noted in all groups, with different levels of significance. The percentage reduction was 46.62% in the resin infiltration group and it was significantly higher than the remaining interventions. Fluoride varnish group had 26.57% reduction, the CPP-ACP group had 28.64% reduction and the control group had 29.75% reduction in the WSL area. Plaque index was noted to have significant correlation with the change in WSL area with higher plaque index scores demonstrating lesser reduction in WSL., Conclusions: The study found that resin infiltration significantly reduced the WSL area after 1-year follow-up. Fluoride toothpaste with or without CPP-ACP and fluoride varnish produced some therapeutic effects., (© 2024. The Author(s), under exclusive licence to British Dental Association.)