Severe Early Childhood Caries (S-ECC) is difficult to treat effectively and has an alarming and distressing tendency to recur following treatment. S-ECC is a particularly acute form of early childhood caries (ECC) that is characterized by an overwhelming caries-promoting microbial challenge, including Mutans Streptococci (MS) and Lactobacilli (LB). The standard of care for ECC/S-ECC revolves around treatment in a surgical operating suite under general anesthesia, followed by application of 5% topical fluoride varnish, family counseling regarding feeding behaviors and oral hygiene instruction. Clinical studies demonstrate approximately 40% of children treated for S-ECC will develop new caries lesions within 12 months after dental surgery. Reducing cariogenic oral microbiota with a topical anti-microbial agent is a potential approach to reduction of recurrent disease in young children with S-ECC. Recent studies have shown that 10% povidone iodine (polyvinylpyrrolidone-iodine, 10% PVPI) appears promising in preventing dental caries in young children. A meta- analysis of antimicrobial interventions and the oral microbiota associated with ECC highlight the paucity of high- quality randomized controlled trials on the efficacy of antimicrobial agents, including PVPI. The data from the National Health and Nutritional Examination Survey (NHANES 2011-2014) indicates that the prevalence of ECC in US preschool children is 24% and ranges between 11% and 72%. The clinical, social and public health impact of ECC/S-ECC is underscored by its association with increased risk of new caries lesions in the primary dentition, a higher risk of caries onset in the permanent dentition, hospitalizations, emergency room visits, high treatment costs, lost school days, diminished ability to learn and a profound impact on a child’s quality of life. The primary objective of this UG3/UH3 application is to assess the efficacy of 10% PVPI in children with S-ECC to prevent, in part or in whole, new cavitated caries lesions that require surgical intervention after oral rehabilitation. The Specific Aims are: 1 (UG3): to finalize the study protocol, develop the Manual of Procedures (MOP), finalize quality management and data management plans, finalize study case report forms (CRFs) and set-up data management system; 2 (UH3): to conduct a single center randomized, double-blind, placebo- controlled Phase II trial (RCT) to evaluate the efficacy of topical 10% PVPI to prevent new cavitated caries lesions when applied to the teeth of children with S-ECC following oral rehabilitation; 3 (UH3): to measure severity and incidence of new dental caries in children with S-ECC following oral rehabilitation who are receiving quarterly topical 10% PVPI; 4 (UH3): to assess the effect of topical 10% PVPI on diversity and composition of oral microbiota, including cariogenic MS, LB and Candida species to better understand the mechanism of action of 10% PVPI on the oral microbiome. The primary outcome wi...