Self-assembling peptide (SAP) P11-4 was introduced to treat initial caries lesions by guiding hydroxyapatite regeneration within the lesion. The objective was to assess the effectiveness in a practical clinical setting. Caries lesions in permanent teeth treated with monomeric and polymeric SAP P11-4 between May 2015 and October 2020 were retrospectively analyzed at the lesion and child levels by bitewing radiography for changes in lesion stage, opacity, and cavitation/restoration. 225 children aged 10–19 years with a total of 413 proximal lesions in posterior teeth, were followed for 0.4–5.5 years (mean (standard deviation): 13 (7) months). Regression occurred in 39% of E1, 37% of E2, and 40% of D1 caries lesions. The proportion of lesions surviving after one year was 0.96 (95% CI: 0.94–0.98), and after two years, it was 0.91 (95% CI: 0.88–0.94). SAP P11-4 is a safe, biomimetic treatment for initial caries lesions in permanent teeth that remineralizes in the deepest zone of a caries lesion and can easily be introduced into routine dental practice. Present real-world clinical data complement and confirm previously published clinical trials, demonstrating that SAP P11-4 is tooth-preserving and can lead to recovery to a healthy tooth stage.