Abstract: We tested the effect of an annual caries preventive intervention, delivered by a fly-in/fly-out oral health professional team, with Indigenous children residing in a remote Australian community. Around 600 Indigenous children aged 5 to 17 years were invited to participate at baseline, of who 408 had caregiver consent. One hundred and ninety-six consented to the epidemiological examination and intervention (Intervention group) and 212 consented to the epidemiological examination only (Comparison group). The intervention, which occurred annually, comprised placement of fissure sealants on suitable teeth, and application of povidone-iodine and fluoride varnish to the whole dentition, following completion of any necessary restorative dental treatment. Standard diet and oral hygiene advice were provided. Caries increment (number of tooth surfaces with new dental caries) in both deciduous and permanent dentitions was measured at the 2-year follow-up. Comparison group children had significantly higher number of new surfaces with advanced caries in the permanent dentition than the Intervention group (IRR = 1.61; 95% CI: 1.02–2.54; p = 0.04); with a preventive fraction of 43%. The effect of intervention remained significant with children in the Comparison group developing significantly more advanced caries lesions in the permanent dentition than the Intervention group children in the adjusted multivariable analysis (IRR = 2.21; 95% CI: 1.03–4.71). Indigenous children exposed to the intervention had less increment in advanced dental caries in the permanent dentition than those not exposed to the intervention.