ObjectivesTo compare the effectiveness of two 5% sodium fluoride (NaF) varnishes containing casein phosphopeptide amorphous calcium phosphate (CPP-ACP) (ClinproTM White) or tricalcium phosphate (TCP) (MI Varnish TM) to the conventional 5% NaF varnish (Duraphat®) in preventing early childhood caries (ECC) in high-risk preschool children. MethodsA double-blinded, randomized controlled trial recruited healthy 3-4-year-old children (N= 582) having at least one carious lesion (pre-cavitated or cavitated) after obtaining written informed consent from parents. Using a computer-generated random-number table, children were assigned to one of the 3 groups: Control group (n= 196): 5% NaF varnish (Duraphat®) or two test groups: 5% NaF with TCP (ClinproTM White) (n= 193) and 5% NaF varnish with CPP-ACP (MI Varnish TM) (n= 193) to receive quarterly (every 3 months) application over 24 months. ResultsIncidence of new caries over 2 years was 59.2% in MI Varnish TM group (n= 125), 65.1% in the ClinproTM White group (n= 129) and 66.1% in the Duraphat® group (n=127) (p= 0.466). The mean cavitated lesions increment was not significant among the 3 groups (p=0.714), as was the mean increment in non-cavitated carious lesions (p= 0.223). There was no significant difference (p= 0.630) in the distribution of total fluoride varnish applications among the three groups. Also, no significant difference was found in comparison of outcomes among the different number of fluoride varnish applications received by children in each group. Conclusions: Both calcium- and phosphate-containing NaF varnishes showed similar efficacy against cavitated and non-cavitated carious lesions as compared to conventional NaF varnish in high-risk preschool children. Clinical Significance: Randomized trial provided a crucial opportunity to advance the understanding of the clinical effectiveness of different fluoride varnishes in preventing early childhood caries. Varnishes containing tricalcium phosphate or casein phosphopeptide amorphous calcium phosphate when compared to sodium fluoride varnish, demonstrated a similar efficacy against early childhood caries in high caries-risk preschool children.