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Objective External apical root resorption ( EARR) is a frequent iatrogenic effect of orthodontic treatment. Substantial variability in responses to postorthodontic EARR has been observed among patients even when similar treatment protocols were used. This observation suggests that environmental and/or genetic variations between individuals may confer susceptibility or resistance to developing EARR. The objective of this study is to determine whether variants in the osteopontin gene, an essential mediator in the odontoclast fusion and attachment process, are positively/negatively associated with postorthodontic EARR. Materials and Methods Genetic screening of eighty-seven orthodontic patients was performed for two polymorphisms in the osteopontin gene cluster (rs9138 and rs11730582). Subjects were divided into groups, according to the presence or absence of EARR (>2 mm). Genotype distributions and allelic frequencies were calculated using the chi-square test. Logistic regression analysis was used to assess the extent to which clinical-related parameters interfered with the EARR. Odds ratios ( OR) and 95% confidence intervals were also calculated. Results Data from this study show that subjects heterozygous and homozygous for the most frequent allele of the osteopontin gene at position 89261521 [ OR: 0.035 ( P = 0.035*) (allele A)] and 89253600 [ OR: 0.20 ( P = 0.025*) (allele T)], respectively, are protected against postorthodontic EARR. Nevertheless, a highly significant association was found in the comparative analysis of homozygous subjects [2/2 ( CC)] for the osteopontin gene (rs9138), resulting in an increased risk of suffering postorthodontic EARR[ OR: 4.10; P = 0.045*; CI: 95%]. Subjects who were homozygous [2/2 ( CC)] for the osteopontin gene (rs11730582) were more likely, and to a greater extent, to be affected with EARR [ OR: 11.68; P < 0.039*; CI: 95%] compared with other genotypes. Conclusion Variations in the osteopontin gene (rs9138 and rs11730582) are determinants of a genetic predisposition to suffer EARR secondary to orthodontic treatment. [ABSTRACT FROM AUTHOR]