OBJECTIVE To compare the effectiveness of fluoride vanish, fluoride foam, pit and fissure sealant with fluoride in prevention of dental caries, and investigate appropriate approach to prevent dental caries at schools. METHODS A randomized controlled clinical trial with 4 parallel groups was conducted. Totally 1016 children from 4 schools and 33 classes with a mean age of 7 to 8 years were included. They were randomly allocated into 4 groups: (1) fluoride vanish, semi-annual application; (2) fluoride foam, semi-annual application; (3) resin sealant, single placement; and (4) placebo control with oral hygiene instruction. Follow-up examinations were conducted after 2 years to monitor dental caries increment of first molars among these children. Data analysis was performed using SPSS 18.0 software package. RESULTS Two years later, 977 children (96.2%) were examined. The results of multiple factor ANCOVA showed that fluoride vanish and resin sealant had significantly lower mean dental caries increment on tooth surface compared with control group (P<0.05). No significant difference of mean dental caries increment on tooth surface was found between fluoride foam and control group (P>0.05). CONCLUSIONS The placement of resin sealant with fluoride and annual application of fluoride protector are effective in prevention of dental caries in permanent teeth of children.