A BSTRACT Background: White spot lesions (WSLs) are considered as the first sign of the progression of dental caries that can be reversed. Casein phosphopeptide–amorphous calcium fluoride phosphate (CPP-ACFP) varnish can promote remineralization process of the demineralized tooth structure. Also, WSLs can be managed by using caries infiltrant (ICON), which infiltrates etched enamel surface of the WSLs. Objectives: The main aim was to evaluate and compare the efficacy of ICON versus CPP-ACFP varnish to treat WSLs in the same oral environments. Materials and Methods: A total of 30 participants aged 20–40 years with at least two WSLs have participated in this trial. Split-mouth technique has been used in this trial where WSLs on the left side have been treated with ICON, whereas WSLs on the right side have been treated with CPP-ACFP varnish. Clinical evaluation using DIAGNOdent was carried out at baseline, 1 week, 1, 3, 6, and 12 months after application to determine the effectiveness of these materials in treating WSLs. Results: Significant differences were observed between all follow-up DIAGNOdent scores compared to baseline readings of both ICON and CPP-ACFP ( P = 0.000 for all comparisons). Statistically significant differences were observed between DIAGNOdent scores of ICON compared to CPP-ACFP at all follow-up intervals ( P = 0.006, 0.008, 0.045, 0.036, and 0.000). Conclusion: Both ICON and CPP-ACFP were effective in the treatment of WSLs of smooth surfaces but the efficacy of CPP-ACFP was better than ICON.