The aim of this study was to compare the effect of two different dental varnishes on approximal caries incidence in teenagers with proven caries susceptibility during a 3-year period. Two hundred 13- to 14-year-old subjects exhibiting at least two approximal enamel caries lesions were selected to take part in the study. One hundred and eighty subjects participated after informed consent and were randomly assigned to two equally sized groups. One group was treated with a fluoride varnish (FV, Fluor Protector) containing 0.1% F every 3rd month and the participants of the other group were treated in the same mode with a chlorhexidine varnish (CV, Cervitec((R))) containing 1% chlorhexidine and 1% thymol. In total, each subject was treated 12 times during the experimental period. Approximal caries including enamel lesions (DMFS(appr)) were recorded from four bitewing radiographs exposed at the start and end of the study. The mean (+/-SD) caries prevalence at baseline was 2.2+/-3.4 in the FV group and 2.5+/-4.0 in the CV group. After 3 years, the average approximal caries incidence was 2.7+/-3.1 and 3.1+/-3.5 in the FV and CV groups, respectively. The differences at baseline and after 3 years were not statistically significant. In conclusion, treatments every 3rd month with either a fluoride- or a chlorhexidine/thymol-containing varnish showed a promising effect with low approximal caries incidence and progression in teenagers with proven caries susceptibility.