Aims: To assess the impact of oral conditions among children/adolescents with Down syndrome (DS) on the Oral Health-related Quality of Life (OHRQoL) of their families in comparison with a group without DS. Methods and Results: Families of 144 children/adolescents with DS aged 4-18 years were compared with families of individuals without DS. Dental caries experience (DMFT/dmft), clinical consequences of untreated dental caries (PUFA/pufa), gingival bleeding (GBI), visible plaque (VPI), and malocclusion were evaluated. Parents/caregivers answered the Family Impact Scale (FIS) and questionnaires on sociodemographic conditions and the health of children/adolescents. Data analysis included chi-square test and Poisson regression. There was no difference between groups regarding the impact of the children's/adolescents' oral condition on their families' OHRQoL for all domains and the total FIS score (P > 0.05). A negative impact on the OHRQoL of families of children/adolescents with DS was determined by dental caries (PR = 3.95, CI = 2.09-7.46), clinical consequences of untreated dental caries (PR = 1.83, CI = 1.18-2.84), defined malocclusion (PR = 2.75, CI = 1.23-6.13), and severe malocclusion (PR = 2.82, CI = 1.02-7.74). Conclusion: There is no difference on the OHRQoL of families of children/adolescents with and without DS. Dental caries experience, clinical consequences of untreated dental caries, defined malocclusion, and severe malocclusion determined the negative impact on the OHRQoL of families of children/adolescents with DS.