Background Evidence supports two methods for preventing dental caries lesions in children: pit and fissure sealants (PFS) and fluoride varnishes (FV). The aim of this study was to compare the cost-effectiveness of these two strategies in preventing dental caries lesions on the occlusal surface of the first permanent molar in children. Methods A Markov model was used to simulate the progression of dental caries on the occlusal surface of the first permanent molar in a hypothetical cohort of children over a 9-year period. Transition probabilities were extracted from the published literature and costs were calculated from a payer’s perspective. Two scenarios were evaluated based on the probability of replacing a failed PFS. Sensitivity analysis was performed to test the robustness of the model. Results Over the 9-year study period PFS were less expensive and more effective than FV in preventing occlusal dental caries lesions. For the base case scenario the probability of replacing a failed PFS was 100 percent and the Incremental Cost-Effectiveness Ratio (ICER) for PFS was $156.87 per first episode of caries lesion averted. For the second scenario, the probability of replacing a failed PFS was lowered to 50 percent. Here, the ICER dropped to $113.00 per first episode of caries lesion averted and remained the dominant strategy. Conclusion PFS should be the preferred method for the prevention of dental caries lesion on the occlusal surface of the first permanent molar, especially in children who are at high risk and have barriers of access to dental care.