Abstract Objectives The present trial’s aim was to compare the remineralization potential of self-assembling peptide P11-4 combined with fluoride to that of fluoride varnish. Materials and methods Twenty-eight participants with 58 incipient carious lesions were enrolled in the present trial. Participants were randomly divided into two groups with 14 participants and 29 incipient lesions in each group. Patients were assigned either to self-assembling peptide combined with fluoride (Curodont Repair Fluoride Plus™) or sodium fluoride varnish (NaF, Bifluorid 10) groups. Both agents were applied according to the manufacturer’s instructions on non-cavitated incipient carious lesions. Lesions were assessed by two calibrated and blinded assessors at baseline, and after one-, three- and six-months using a laser fluorescence device (DIAGNOdent). Results Although laser fluorescence scores significantly improved in both groups over time (p < 0.05), no notable differences were evident between both groups at one-month (p > 0.05). Yet, at three- and six-months statistically lower laser fluorescence readings were evident in the self-assembling peptide combined with fluoride group in comparison to the fluoride alone group (p < 0.05). There was 60% less risk for caries progression for Curodont Repair Fluoride Plus™ when compared to NaF varnish after six months. Self-assembling peptide combined with fluoride was able to change 65.5% of non-cavitated carious lesions from DIAGNOdent score 3 (11–20) to score 1 (0–4). Fluoride varnish was able to change 13.8% of the lesions from score 3 to score 1 after six months. Conclusions The self-assembling peptide combined with fluoride varnish showed higher remineralization potential than fluoride varnish alone for incipient carious lesions over a six-months follow up. Clinical relevance The combination of self-assembling peptide P11-4 and fluoride could offer a new tool in managing incipient carious lesions.