This study evaluated whether toddlers in an extended preventive program of semiannual fluoride varnish applications from 1 year of age had a lower incidence of caries than those undergoing a standard program. A cohort of 1-year-old children (n = 3,403) living in multicultural areas of low socioeconomic standing in Stockholm participated in a cluster-randomized controlled field trial with two parallel arms. The children attended 23 dental clinics. Using the ICDAS II criteria, the examiners recorded caries at baseline and after 1 and 2 years. The children in the reference group received a standardized oral health program once yearly between 1 and 3 years of age. The children in the test group received the same standard program supplemented with topical applications of fluoride varnish every 6 months. We compared the test group and the reference group for the prevalence and increment of caries. At baseline, 5% of the children had already developed caries (ICDAS II 1-6). We reexamined the children after 1 year (n = 2,675) and after 2 years (n = 2,536). Neither prevalence nor caries increment differed between the groups. At 3 years of age, 12% of the children had developed moderate and severe carious lesions (ICDAS II 3-6), with a mean increment of 0.5 (SD 2.4) in the test group and 0.6 (SD 2.2) in the reference group. In conclusion, semiannual professional applications of fluoride varnish, as a supplement to a standard oral health program, failed to reduce caries development in toddlers from high-risk communities.