Purpose: Hypomineralized primary second molars (HPSMs) are clinically represented by demarcated opacities in the enamel, involving from one to four primary second molars. The purpose of this cross-sectional study was to investigate the systemic exposures associated with hypomineralized primary second molars. Methods: A representative population-based sample of 731 eight-year-old children was randomly selected. Data on systemic exposures were collected via a structured questionnaire given to the children's mothers. The HPSMs were clinically assessed by calibrated examiners according to the modified-DDE (developmental defects of enamel) index and European Academy of Paediatric Dentistry criteria. Associations were analyzed by Poisson multiple regression considering a temporal hierarchical approach. Results: The prevalence of HPSMs was 9.4 percent (95 percent confidence interval equals 7.0 to 12.0 percent). Children whose mothers presented with hypertension were found with an Adjusted Prevalence ratio (PRa) of 1.73 (P=0.044) and mothers who used tobacco (PRa equals 2.44; P=0.001) during pregnancy had a significantly higher prevalence of HPSMs. The presence of complications during delivery (PRa equals 1.83; P=0.032) and the occurrence of otitis media during early childhood (PRa equals 1.68; P=0.043) also presented a higher prevalence of HPSMs. Conclusion: The use of tobacco, presence of hypertension, complications during delivery, and otitis media during the first years of a child's life are associated with a higher prevalence of hypomineralized primary second molars. (Pediatr Dent 2019;41(5):364-70).