This study aims to investigate the effect of topical applications of 10% casein phosphopeptide-amorphous calcium phosphate (CPP-ACP) on white spot lesions (WSL) detected after treatment with fixed orthodontic appliances. Sixty healthy adolescents with ≥1 clinically visible WSL at debonding were recruited and randomly allocated to a randomised controlled trial with two parallel groups. The intervention group was instructed to topically apply a CPP-ACP -containing agent (Tooth Mousse, GC Europe) once daily and the subjects of the control group brushed their teeth with standard fluoride toothpaste. The intervention period was 4 weeks and the endpoints were quantitative light-induced fluorescence (QLF) on buccal surfaces of the upper incisors, cuspids and first premolars and visual scoring from digital photos. The attrition rate was 15%, mostly due to technical errors, and 327 lesions were included in the final evaluation. A statistically significant (p < 0.05) regression of the WSL was disclosed in both study groups compared to baseline, but there was no difference between the groups. The mean area of the lesions decreased by 58% in the CPP-ACP group and 26% in the fluoride group (p = 0.06). The QLF findings were largely reflected by the clinical scores. No side effects were reported. Topical treatment of white spot lesions after debonding of orthodontic appliances with a casein phosphopeptide-stabilised amorphous calcium phosphate agent resulted in significantly reduced fluorescence and a reduced area of the lesions after 4 weeks as assessed by QLF. The improvement was however not superior to the "natural" regression following daily use of fluoride toothpaste.