Purpose: This study's purpose was to investigate whether polymorphisms in the HIF-1 encoding gene and hypoxia-related environmental factors were associated with hypomineralized second primary molars (HSPMs). Methods: From a total of 731 children from Curitiba, Paraná, Brazil, were selected, the prevalence of HSPMs in this population was 9.4 percent, representing 69 cases (HSPMs) and 662 controls. The environmental factors were collected via questionnaire. HSPMs were evaluated by calibrated examiners. Two genetic polymorphisms (rs2301113 and rs2057482) in the HIF-1 gene were genotyped by polymerase chain reaction in real time. Associations were tested by Poisson regression analysis (Prevalence Ratioadjusted; P<0.05). Results: In the multiple variable model, including the environmental factors and genetic polymorphisms, maternal use of an illicit drug (Prevalence Ratioadjusted; equals 4.52; P<0.001; 95 percent confidence interval [95% CI] equals 2.38-8.53), maternal diseases during pregnancy (Prevalence Ratioadjusted; equals 1.97; P=0.034; 95% CI equals 1.05 to 3.71), and respiratory diseases during childhood (Prevalence Ratioadjusted; equals 2.66; P=0.003; 95% CI equals 1.41 to 5.03) increased significantly the prevalence of HSPMs. In the presence of environmental factors, individuals carrying at least one C allele in rs2057482 had a lower prevalence of HSPMs (Prevalence Ratioadjusted; equals 0.51; P=0.048; 95% CI equals 0.27 to 0.99). Conclusions: Children who had hypoxia-related factors presented with a higher prevalence of hypomineralized second primary molars. A C allele in rs2057482 served as protection against HSPMs in hypoxia conditions.