The present study aimed to evaluate the association between premature primary tooth loss and oral health-related quality of life (OHRQoL) in preschool children. A cross-sectional study was conducted in 769 5-year-old preschool children. The children and their parents or guardians answered the Brazilian version of the Scale of Oral Health Outcomes for 5-Year-Old Children for the assessment of OHRQoL. Meanwhile, clinical examinations were performed for the assessment of premature primary tooth loss. Unadjusted and adjusted multilevel Poisson regression models were utilized to investigate the associations between the variables. In the parental version of the scale, premature posterior primary tooth loss (rate ratio RR = 2.65; 95% confidence interval CI = 1.51-4.68), weak sense of coherence (RR = 2.25; 95% CI = 1.62-3.11), and visit to a dentist (RR = 1.61; 95% CI = 1.04-2.52) were associated with OHRQoL. Based on the children's perceptions, only the preschool type was associated with OHRQoL (RR = 1.92; 95% CI = 1.21-3.05). Premature posterior primary tooth loss had a greater impact on OHRQoL based on the parents' perception, whereas only the preschool type was associated with OHRQoL based on the children's perception.