Background: Excessive fluoride exposure has been associated with intelligence loss, but little is known about gene-fluoride interactions on intelligence at SNP-set, gene and pathway level. Objectives: Here we conducted a population-based study in Chinese school-aged children to estimate the associations of fluoride from internal and external exposures with intelligence as well as to explore the gene-fluoride interactions on intelligence at SNP-set, gene and neurodevelopmental pathway level. Methods: A total of 952 resident children aged 7 to 13 were included in the current study. The fluoride contents in drinking water, urine, hair and nail were measured using the ion-selective electrode method. LASSO Binomial regression was conducted to screen the intelligence-related SNP-set. The gene-fluoride interactions at gene and pathway levels were detected by the Adaptive Rank Truncated Product method. Results: The probability of high intelligence was inversely correlated with fluoride contents in water, urine, hair and nail (all P