Objective: To compare the caries preventive effects of 2-year application of school-based chlorhexidine varnish, sodium fluoride gel, and dental health education programs among a high-risk group of 11- to 13-year-olds with low caries activity. Method and Materials: A total of 149 subjects who had previous caries experience in the primary dentition and Streptococcus mutans levels higher than 105 at baseline with 0 DMFS index were selected for this randomized clinical trial. Subjects were allocated to one of 3 groups for treatment with chlorhexidine varnish (n = 50), sodium fluoride gel (n = 50), or a dental health education program (n = 49), which were repeated throughout the 2-year study. The outcomes examined at the end of the study were the caries increment (DMFS index), dental plaque scores, and salivary S mutans counts. Results: The subjects in the education group showed a significant increase in the salivary levels of S mutans in comparison with the other groups (P = .004), but there was no significant difference among the groups in the caries increment after 2 years, with mean DMFS ± SD as 0.95 ± 1.33, 0.88 ± 1.47, and 1.05 ± 2.01 in the chlorhexidine varnish, sodium fluoride gel, and education groups, respectively. There were also no significant differences in the pre- and posttreatment plaque scores between the groups. Conclusion: Although all 3 preventive programs in this high-caries-risk group of children with low caries activity resulted in similar plaque and caries values after 2 years, longer follow-up studies are needed to clarify the effect of reduction in S mutans growth by chemotherapeutic agents in caries incidence. Keywords: caries, chlorhexidine, education, fluoride, Streptococcus mutans