Purpose: To evaluate the perception of caregivers of individuals with Down syndrome (DS) regarding the impact of oral conditions on their children's oral health-related quality of life (OHRQoL) and compare with the perception of caregivers of children without DS.<br/> Methods: This is a comparative cross-sectional study. Participants were 144 four- to 18-year-old children with DS, matched by sex and age with a group without DS, and their caregivers. The children were assessed for dental caries experience, clinical consequences of untreated dental caries, gingival bleeding, visible plaque, and malocclusion. Caregivers answered a questionnaire on sociodemographic conditions and completed the Parental-Caregiver Perceptions Questionnaire (P-CPQ). Data analysis included the Wilcoxon test, chi-square test, and Poisson regression (PR).<br/> Results: Caregivers of individuals with DS presented more negative perceptions of their children's OHRQoL in the functional limitations domain (P<0.01) and in the total P-CPQ score (P=0.02). The determining factors were clinical consequences of untreated dental caries (PR=1.72; 95 percent confidence interval [95% CI]=1.04 to 2.84) and visible plaque (PR=1.48; 95% CI=1.08 to 2.03).<br/> Conclusion: Caregivers of individuals with DS presented more negative perceptions of the impact of oral conditions on their children's OHRQoL. Clinical consequences of untreated dental caries and visible plaque were the determining factors with the greatest impact on the perception of their children's OHRQoL.