Non-invasive caries treatment is a major focus in modern dentistry. The present study was designed to evaluate the effectiveness of monomeric self-assembling peptide P 11-4 (SAP P 11-4) in combination with fluoride varnish or polymeric self-assembling peptide matrix (SAPM) in treatment of non-cavitated occlusal caries. Ninety children and adolescents were included in this randomized, gold-standardcontrolled clinical trial. Test Group 1 received SAP P 11-4 and twice fluoride varnish at baseline and Day 180, Test Group 2 received SAP P 11-4 on baseline and twice weekly SAPM (home-application), and Control Group received fluoride varnish on baseline and Day 180. Caries progression was measured by laser fluorescence, Nyvad Caries Activity, ICDAS-II-codes, and investigator assessments. Laser fluorescence changes demonstrated superior results for Test Group 1 and 2, as values decreased compared to an increase for the Control Group (p < 0.0005). ICDAS-II codes at Day 360 showed partial regression for Test Group 1 (6.7%) and Test Group 2 (20.0%) and partial progression for Control Group (23.3%) (p < 0.01). Nyvad Caries Activity yielded superior caries inactivation for Test Groups, compared to Control Group (p = 0.002). This trial showed that SAP P 11-4, applied either in combination with fluoride varnish or twice weekly SAPM, was a superior treatment for early caries compared to fluoride varnish alone. Caries levels have significantly decreased over the past decades, partially due to the introduction of fluoride in various forms 1. However, despite the promising efforts and results worldwide, caries levels have remained high, and caries is still the most common disease worldwide 2. Recent efforts to lower caries levels have focused on treating early carious lesions non-invasively, as there is consensus that only early intervention, prior to cavitation, can lead to a regression of the caries to a more healthy state 3,4. Novel therapeutics have been called for, and promising approaches are based on biomimetic research and development. Biomimetic concepts fall into two categories, either based on amelogenin or derivatives thereof, or on rationally designed and screened systems 5,6. There is substantial research in the field, yet most of it is in vitro-based. The exceptions are recent clinical investigations of the rationally designed self-assembling peptide P 11-4 applied either in its monomeric form (SAP P 11-4) 5,6 or its polymeric form as a self-assembled peptide matrix (SAPM). This is the first clinical trial investigating the combined effect of SAP P 11-4 and SAPM in treatment of early carious lesions. SAP P 11-4 has been systematically investigated 7. The self-assembling peptide was rationally designed to provide favourable physicochemical characteristics for nucleation of hydroxyapatite (HA) on the surface of the formed fibres of the 3D matrix 8,9. The mechanism of action of SAP P 11-4 in the remineralization of enamel was proposed early on and has been proven since 10,11. When monomeric SAP P 11-4 is applied onto th...