INTRODUCTION: A systematic review of evidence on the impact of modifiable risk factors on early childhood caries (ECC) was conducted to inform recommendations in a World Health Organization manual on ECC prevention. OBJECTIVES: To systematically review published evidence pertaining to the effect of modifiable risk factors on ECC. METHODS: Twelve questions relating to infant feeding, diet, oral hygiene, and fluoride were addressed, as prioritized by a World Health Organization expert panel. Questions pertaining to the use of fluoride toothpaste were excluded due to its proven efficacy. The target population was children aged <72 mo. Data sources included Medline, Embase, CINAHL, and PubMed, and all human epidemiologic studies were included. The highest level of evidence was used for evidence synthesis and, where possible, meta-analysis. The review was conducted in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) statement, with evidence assessed via the GRADE method. RESULTS: Of the 13,831 papers identified, 627 were screened in duplicate; of these, 139 were included. The highest-level evidence indicated that breastfeeding ≤24 mo does not increase ECC risk but suggested that longer-duration breastfeeding increases risk (low-quality evidence). Low-quality evidence indicated increased risk associated with consumption of sugars in bottles. Only 1 study had data on the impact of sugars in complementary foods, which increased risk. Moderate-quality evidence showed a benefit of oral health education for caregivers (odds ratio, 0.39; 95% CI, 0.19 to 0.80, P = 0.009). Meta-analysis of data on the impact on ECC from living in a fluoridated area showed a significant effect (mean difference, -1.25; 95% CI, -1.24 to -0.36; P = 0.006). Limited moderate- and low-quality data indicated a benefit of fluoride exposure from salt and milk, respectively. CONCLUSION: The best available evidence indicates that breastfeeding up to 2 y of age does not increase ECC risk. Providing access to fluoridated water and educating caregivers are justified approaches to ECC prevention. Limiting sugars in bottles and complementary foods should be part of this education. KNOWLEDGE TRANSFER STATEMENT: This research is being used by the World Health Organization in developing a toolkit on the prevention and management of early childhood caries. The information will guide 1) governments in developing national oral health plans and 2) clinicians when providing preventive advice, including that regarding infant feeding practices. It will help ensure that advice is in line with current World Health Organization guidelines and the best available evidence.