OBJECTIVES: To compare the effect of self-assembling peptide P11-4 with fluoride, casein phosphopeptide amorphous calcium phosphate fluoride (CPP-ACPF) varnish and 5% sodium fluoride varnish (NaF), on Streptococcus mutans (S. mutans) in dental plaque of preschoolers in addition to assessing change in plaque index after their intensive application. METHODS: Sixty-six preschoolers were randomly assigned into three groups to receive triple applications of P11-4 with fluoride, CPP-ACPF varnish or NaF. S. mutans count in supragingival plaque samples was assessed at baseline (T0) and after the third application by 48 h (T1), one month (T2) and 3 months (T3). Multivariable linear regression compared the effect of these materials on S. mutans log count at various time intervals. Baseline plaque index was compared to that at T2 and T3. RESULTS: All study groups presented a significant decrease in S. mutans count at T1, T2 and T3. Multivariable linear regression demonstrated a significant more reduction in S. mutans count in CPP-ACPF and NaF groups when compared to P11-4 with fluoride at T1. At T2 and T3, CPP-ACPF showed superior reduction in bacterial count than NaF and P11-4 with fluoride, with no significant difference between the latter two materials. Plaque index was significantly reduced at all study groups at T2 and T3, with CPP-ACPF being the most proficient. CONCLUSION: CPP-ACPF presented superior antibacterial effect when compared to P11-4 with fluoride or NaF which exhibited comparable antibacterial effect. CLINICAL RELEVANCE: Different remineralizing agents can have additive antibacterial effect against S. mutans that affects individual's future caries experience.