This case-control study investigated risk factors for enamel fluorosis in optimally fluoridated children, born after the US infant formula industry voluntarily reduced the fluoride content of their products. Analysis was performed on 233 children, aged 10-14 years. Case-control status was determined using the Fluorosis Risk Index (FRI). Risk factor exposure was ascertained via a mailed questionnaire. Logistic regression analyses revealed a strong association between mild-to-moderate enamel fluorosis on early forming (FRI classification I) enamel surfaces and both fluoride supplement use (odds ratio (OR)=5.95, 95% confidence interval (CI) 1.06-33.53), and early fluoride toothpaste use (OR=6.35, 95% CI 1.21-33.40). The authors found a suggestive, but nonsignificant, association between fluorosis on these enamel surfaces and infant formula in the form of powdered concentrate (OR=4.33, 95% CI 0.73-25.66). There was a strong association between mild-to-moderate fluorosis on later forming (FRI classification II) enamel surfaces and infant formula use in the form of powdered concentrate (OR=10.77, 95% CI 1.89-61.25), fluoride supplement use (OR=10.83, 95% CI 1.90-61.55), and early fluoride toothpaste use (OR=8.37, 95% CI 1.68-41.72). No association was observed between the use of ready to feed infant formula and enamel fluorosis.