Background: Molar hypomineralization (MH) is defined as a multifactorial condition, and thus, its presence may be defined by interactions between environmental and genetic factors. Aim: To evaluate the association between MH, genes involved in enamel development, and the use of medication during pregnancy in early childhood. Design: One hundred and eighteen children, 54 with and 64 without MH, were studied. The data collected included demographics, socioeconomic data, and the medical history of mothers and children. Genomic DNA was collected from saliva. Genetic polymorphisms in ameloblastin (AMBN; rs4694075), enamelin (ENAM; rs3796704, rs7664896), and kallikrein (KLK4; rs2235091) were evaluated. These genes were analyzed by real-time polymerase chain reaction using TaqMan chemistry. The software PLINK was used to compare allele and genotype distributions of the groups and to assess the interaction between environmental variables and genotypes (p < .05). Results: The variant allele KLK4 rs2235091 was associated with MH in some children (odds ratio [OR]: 3.75; 95% confidence interval [CI] = 1.65–7.81; p = .001). Taking medications in the first 4 years of life was also associated with MH (OR: 2.94; 95% CI = 1.02–6.04; p = .041) and specifically in association with polymorphisms in ENAM, AMBN, and KLK4 (p < .05). The use of medications during pregnancy was not associated with MH (OR: 1.37; 95% CI = 0.593–3.18; p = .458). Conclusion: The results of this study suggest that taking medication in the postnatal period appears to contribute to the etiology of MH in some evaluated children. There may be a possible genetic influence of polymorphisms in the KLK4 gene with this condition.