This study aimed to evaluate the effect of self-assembling peptide P 11 -4 (SAP) in the therapy of initial smooth surface caries (white spot lesions, WSL) following orthodontic multibracket treatment. Twentythree patients (13f/10m; average age 15.4 years) with at least two teeth with WSL were recruited for the randomised controlled clinical trial with split-mouth design. In opposite to the control teeth, the test teeth were treated with SAP on Day 0. The primary endpoint was the impedance measurement of WSL using customised tray to ensure reproducibility of the measurement location. The secondary endpoint was the morphometric measurement of WSL using a semi-automated approach to determine the WSL size in mm 2 . Treatment effects were adjusted for site-specific baseline values using mixed models adapted from the cross-over design. Test WSL showed a mean baseline impedance value of 46.7, which decreased to 21.1, 18.4, and 19.7 after 45, 90, and 180 days, respectively. Control WSL showed a mean baseline value of 42.0, which decreased to 35.0, 29.5, and 33.7, respectively. The overall treatment contrast was −13.7 (95% CI: −19.6 -−7.7; p < 0.001). For the secondary endpoint, the test WSL size decreased from 8.8 at baseline to 6.5 after 180 days. The control WSL decreased from 6.8 to 5.7, respectively. The related treatment contrast was −1.0 in favour of test WSL (95% CI: −1.6 -−0.5; p = 0.004). The treatment of initial carious lesions with self-assembling peptide P 11 −4 leads to superior remineralisation of the subsurface lesions compared with the control teeth.Orthodontic treatments with fixed multibracket appliances hindering oral hygiene, support plaque accumulation, and caries progression 1,2 . These orthodontic treatment-induced carious lesions are typically visible first as so-called white spot lesions (WSL) on the buccal surface of the tooth outlining the brackets 3-6 .Modern treatment concepts for caries emphasise tooth preservation and remineralisation concepts especially for initial non-cavitated carious lesions, in order to hinder or to delay the first invasive intervention, meaning destruction of the natural tooth structure 7 .Unique for buccal WSL is the addition of an aesthetic component to the cariological issue 3,8 . Fluorides prevent the formation of so-called white spot lesions (WSL) but have shown little effect on the reduction of existing WSL 9-11 . As their effect is restricted to the outer surface layer of the enamel (i.e. top 50 µm) and does not promote the remineralisation throughout the demineralised lesion body. The WSL persist visually almost unchanged 12-14 . Other remineralisation agents, often based on calcium phosphate, have been investigated, but could not show clinically significant advantage over fluoride 10,11,[15][16][17] .As a consequence, new treatment approaches have been called for and biomimetic mineralisation seems to be one promising possibility [18][19][20][21][22] . However, the only clinically available products at present are based on the self-assembling peptide P 11 -4 ...