This systematic review aimed to determine the caries-inhibiting effect of chlorhexidine (CHX) varnishes on the permanent dentition of children, adolescents and young adults, and to explore two possibly related factors, namely application frequency and the time between evaluation and the last application. The literature search identified 14 publications of randomized controlled trials or controlled clinical trials where the effect of CHX varnish was compared with placebo controls or controls that received no preventive treatment. To obtain uniform outcome effects, the prevented fraction and 95% confidence intervals of caries increment were calculated. Owing to insufficient data presentation, only eight publications were included. Another two publications were included after receiving additional data from the authors. This systematic review did not result in a meta-analysis as an overall prevented fraction could not be computed because of the large variation of outcome results. The variation could not be explained by the time between evaluation and last application but might be explained by application frequency. It is tentatively concluded that CHX varnish has a moderate caries-inhibiting effect when applied every 3-4 months. However, this effect seems to have diminished by around 2 yr after the last application. There is no evidence for a caries-inhibiting effect of CHX varnish with longer intervals between applications.