The aim of this study was to assess the efficacy of CPP-ACP in reducing salivary S. mutans levels and compare its effect as a dentifrice to use of a fluoride dentifrice alone, or with the sequential use of a combination of both agents (fluoride, then CPP-ACP) in three groups of preschool children over a 6-month period.This was a double-blinded clinical trial, the sample (n = 127, age 4.6 ± 0.47 years), with high caries risk, was randomized into three groups which applied different agents twice daily; fluoride toothpaste (500 ppm, n = 50), CPP-ACP (10% w/v, n = 38), and combination group (n = 39) applied fluoride, then CPP-ACP. S. mutans salivary levels were measured by GC Saliva-Check Mutans.Within groups, a significant decrease in S. mutans-positive children (SMPC) occurred in fluoride and combination groups at 3-months, (P < 0.05), and in all groups at 6-months, (P < 0.05). The highest reduction in SMPC occurred in the CPP-ACP group, however, there were no significant differences in SMPC between groups at all study intervals, (P > 0.05).Although all agents were effective, CPP-ACP showed the highest reduction in SMPC over 6-months.