BackgroundSelf-assembling peptide (SAP) P11-4 was introduced to treat initial caries lesions by means of guiding hydroxyapatite regeneration within the lesion. The objective of this study was to assess its effectiveness in a practical clinical setting. MethodsCaries lesions in permanent teeth treated with monomeric and polymeric SAP P11-4 from May 2015 through October 2020 were retrospectively analyzed at lesion and child levels by means of bite-wing radiography for changes in stage and cavitation and restoration. ResultsTwo hundred and nineteen children aged 10 through 19 years with a total of 405 proximal lesions in posterior teeth were followed from 0.4 through 5.5 years (median, 7 months; interquartile range, 6-19 months). Regression occurred in 37% of stage RA1 (radiolucency in the outer one-half of enamel) (95% CI, 31% to 44%), 38% of stage RA2 (radiolucency in the inner one-half of enamel plus or minus the enamel–dentin junction) (95% CI, 30% to 45%), and 40% of stage RA3 (radiolucency limited to the outer one-third of dentin) (95% CI, 16% to 68%) lesions. The proportion of lesions with no cavitation was 0.96 (95% CI, 0.94 to 0.98) after 1 year and 0.91 (95% CI, 0.88 to 0.95) after 2 years. ConclusionsReal-world clinical data indicate that SAP P11-4 can lead to recovery and a healthier tooth stage. Practical ImplicationsSAP P11-4 is a safe treatment for initial caries lesions in permanent teeth that remineralizes in the deepest zone of the lesion and can be introduced easily into routine dental practice.