A professionally applied two-stage chlorhexidine varnish, Chlorzoin((R)), was developed to achieve sustained release and minimise the problems of staining and bad taste associated with chlorhexidine mouthrinses. The primary aim of this randomised controlled clinical trial was to assess the efficacy of Chlorzoin in reducing the caries increment in high-caries-risk adolescents. Secondary aims included investigating the effect of compliance upon caries increment, the effect of Chlorzoin upon salivary mutans streptococci levels and assessing the benefit of individual dental health advice by dental auxiliaries in a community setting. 1,240 children, initially aged 11-13 years, assessed to be at high caries risk were recruited into the trial. The trial design involved four arms: an observational group, a control group, an active (Chlorzoin) varnish group and a placebo varnish group. All subjects were examined annually by a calibrated examiner who was blind to the group allocation. Three-year caries increments were calculated using clinical, clinical and fibre-optic transillumination, and clinical and bitewing data sets. The results indicated that the use of Chlorzoin had an initial effect on mutans streptococci levels but that no long-term reduction in caries increment or mutans streptococci infection could be detected. One reason for this lack of efficacy may have been the regimen of reduced frequency of varnish applications after the initial period. Children who followed the protocol and, therefore, were seen regularly by dental auxiliaries had a lower caries increment than those who did not. This finding was independent of varnish allocation. In summary, under this regimen, Chlorzoin has been found to be effective in decreasing salivary mutans streptococci but ineffective as a caries-preventive agent in high-risk Scottish children when applied pragmatically in a community setting.