The aim of this 2-year prospective randomized clinical study was to evaluate the efficacy of a prevention program for schoolchildren with high caries risk. A sample of 419 subjects was divided into a test (T, n = 259) and control group (C, n = 160). Four times a year, the test group received professional tooth-cleaning and application of a 0.1% fluoride varnish as well as motivation and instruction in oral hygiene. The control group received only oral hygiene instruction and took part in supervised toothbrushing once a year. At baseline and after 2 years, the D3,4MFS and the incipient lesions (D1,2) were recorded. After 2 years, 318 subjects (T = 187, C = 131) were included in the data analysis. The baseline D1,2 was 6.18 (T) and 5.50 (C), the D3,4MFS 2.13 (T) and 2.08 (C), respectively. No statistically significant difference was found for the baseline values. At the final examination, the D1,2 increment was 3.96 in the test and 6.53 in the control group, showing a statistically significant difference (P < 0.001). No such difference was found for the D3,4MFS increment (T: 2.22; C: 2.61). The results indicate that it might not be possible to prevent cavities in high caries risk children by means of the described program.