This cluster-randomized controlled community trial aimed to assess the efficacy and costs of fluoride varnish (FV) application for caries prevention in a high-risk population in South Africa. 513 children aged 4-8years from two schools in a township in South Africa were randomly allocated by class to the FV or Control (CO) groups. In addition to supervised toothbrushing with fluoridated toothpaste in both groups, FV was applied in 3-month intervals by trained local non-professional assistants. Intraoral examinations were conducted at baseline, 12, 21 and 24months. Primary outcome was the increment of teeth with cavitated lesions (i.e. newly developed or progressed, formerly non-cavitated lesions), requiring restoration or extraction over the study period. Additionally, treatment and re-treatment costs were analyzed. 513 children (d1-4 mft 5.9±4.3 (mean±SD)) were randomly allocated to FV (n=287) or CO (n=226). 10.2% FV and CO teeth received or required a restoration; 3.9% FV and 4.1% CO teeth were extracted, without significant differences between groups. While FV generated high initial costs, follow-up costs were comparable in both groups, resulting in FV being significantly more expensive than CO (1667±1055 ZAR vs. 950±943 ZAR, p<.001). Regular FV application, in addition to daily supervised toothbrushing, had no significant caries-preventive effect and was not cost-effective in a primary school setting within a peri-urban, high-risk community in South Africa. Alternative interventions on community or public health level should be considered to reduce the caries burden in high-risk communities.